Research grants 2016–2024

MND Research Australia awarded over $3.1 million towards motor neurone disease research projects commencing in 2024. The grants awarded include the Daniel McLoone MND Research Prize, three postdoctoral fellowships and 18 Innovator grants.

Fellowships

Daniel McLoone MND Research Prize (2024–25)
Lead investigator: Dr Chien-Hsiung (Alan) Yu
Institution: University of Melbourne
Title: Investigating TDP-43-associated immune activation to map the causes of MND

Bill Gole MND Postdoctoral Fellowship (2024–26)
Lead investigator: Dr Rachel Atkinson
Institution: University of Tasmania
Title: Freezing MND in its tracks

Jim Zissimopoulos MND Postdoctoral Fellowship (2024–26)
Lead investigator: Dr Nicole Sheers
Institution: University of Melbourne
Title: Developing a new exercise therapy to improve breathing and cough in people living with MND

David Deguara MND Postdoctoral Fellowship (2024–26)
Lead investigator: Dr Thais Sobanski 
Institution: The University of Queensland  
Title: Boosting sugar breakdown to halt the progression of MND

Innovator grants

Charcot Award (supported by MonSTaR)
Lead investigator: Dr Adekunle Temitope Bademosi
Institution: University of Queensland
Title: Investigating the role of synaptic proteins in MND neurodegeneration

Superball XVI MND Research Grant
Lead investigator: Dr Samantha Barton
Institute: University of Melbourne
Title: Could Schwann cells be exacerbating motor neuron dysfunction in MND?

Daniel Veysey MND Research Grant
Lead investigator: Dr Mouna Haidar
Institute: University of Melbourne
Title: Assessing the therapeutic impact of chemogenetic stimulation of neuropeptide Y cortical interneurons in ALS mouse models

Daniel McLoone MND Research Grant
Lead investigator: Dr Wei Luan
Institution: University of Queensland
Title: Synaptic mechanisms of non-motor dysfunction in MND

Daniel McLoone MND Research Grant
Lead investigator: Dr Sarah Rea
Institution: Murdoch University
Title: Antisense oligonucleotide induced clearance of cytoplasmic TDP-43 aggregates to prevent disease progression in ALS

Jenny Simko MND Research Grant
Lead investigator: Dr Luke McAlary
Institution: University of Wollongong
Title: Deep mutational scanning to define and predict the pathogenicity of existing and future SOD1 mutations

Peter Stearne Familial MND Research Grant
Lead investigator: Dr Ianthe Pitout
Institution: Murdoch University
Title: Developing a New Drug Candidate for C9ORF72-linked MND

Run MND NSW Research Grant
Lead investigator: Dr Sayanthooran Saravanabavan
Institution: Macquarie University 
Title: Examining the pathogenic roles of circular RNAs in genomic instability in ALS

Dr Paul Brock MND NSW Research Grant
Lead investigator: Dr Rachel Tan
Institution: University of Sydney
Title: Accessible disease-specific biomarkers for sporadic MND

Daniel McLoone MND Research Grant
Lead investigator: Dr Benjamin Trist
Institution: University of Sydney
Title: Partnering with industry to develop new assays for improving diagnosis, understanding and treatment of ALS

Daniel McLoone MND Research Grant
Lead investigator: Professor Yuling Wang
Institution: Macquarie University
Title: Investigating the role of extracellular vesicles (EVs) membrane

Peter Gregory & Fore Group MND Research Grant
Lead investigator: Associate Professor Richard Gordon
Institute: Queensland University of Technology
Title: Harnessing the immune system to resolve neuroinflammation and promote motor neuron survival in MND

Bruce Catto MND Research Grant
Lead investigator: Dr Cindy Maurel
Institution: Macquarie University
Title: Probing molecular drivers of TDP-43 phase transition: the influence of lysine modifications

Doug Parry MND Research Grant
Lead investigator: Associate Professor Marco Morsch
Institution: Macquarie University
Title: Targeting the nucleus: Is TDP-43 supplementation in the nucleus enough to delay disease progression?

Fat Rabbit MND Research Grant
Lead investigator: Dr Hazel Quek
Institution: The Council of the Queensland Institute of Medical Research
Title: Microglia Diversity in ALS: Impact on Disease and Drugs

Murray Geale MND Research Grant
Lead investigator: Dr Alain Wuethrich
Institution: The University of Queensland
Title: Developing a new nanotechnology to track ALS

NTI MND Research Grant
Lead investigator: Dr Rebecca San Gil
Institution: The University of Queensland 
Title: Targeting protein aggregation in motor neuron disease

Col Bambrick MND Research Grant
Lead investigator: Dr Andrew Tosolini
Institution: The University of Queensland 
Title: Connecting the dots between the powerhouse of the motor neuron and their vulnerability in MND

MNDRA PhD Scholarship Top-Up Grants (2024–2026)

Lead investigator: Flora Cheng
Institution: Macquarie University
Title: Identification and characterisation of RNA-protein interaction in pathological aggregates of TDP-43 in MND

Lead investigator: Stephanie Howe
Institution: University of Queensland
Title: Characterising the spatio-temporal landscape of neuroinflammation and metabolism in ALS

Lead investigator: Andrew Quattrocchi
Institution: The University of Melbourne
Title: Understanding and modelling the neurovascular niche in health and MND

For research commencing in 2023, the MNDRA Research Committee awarded $2,994,675 across 21 research projects, including two $1 million Daniel McLoone Major Research Initiatives, in collaboration with FightMND.

Daniel McLoone Major Research Initiative (2023–26)
Lead investigator: Dr Thanuja Dharmadasa
Institution: University of Melbourne and the Florey Institute of Neuroscience
Title: Exploring disease heterogeneity across MND clinical phenotypes using a multimodal, multicentre neuroimaging approach

Daniel McLoone Major Research Initiative (2023–26)
Lead investigator: Professor Brad Turner
Institution: University of Melbourne and the Florey Institute of Neuroscience
Title: Australian Preclinical Research ALS (APRALS) Network: a roadmap for effective translation of therapeutics for sporadic MND

Daniel McLoone MND Research Prize (2023–24)
Lead investigator: Dr Catherine Blizzard
Institution: University of Tasmania
Title: A collaborative multivariable approach to prevent the spread of corticomotor dysfunction in ALS

Bill Gole MND Postdoctoral Fellowship (2023–25)
Lead investigator: Dr Jeremy Lum
Institution: University of Wollongong
Title: Identifying drivers that contribute to the loss of neuronal connections in the early stages of ALS

Beryl Bayley MND Postdoctoral Fellowship (2023–25)
Lead investigator: Dr Alison Hogan
Institution: Macquarie University
Title: The RNA-binding protein SFPQ offers a novel avenue to understand disease mechanisms and identify therapeutic targets in MND

Charcot Award
Lead investigator: Professor Trent Woodruff
Institution: University of Queensland
Title: Linking C9orf72 dipeptides to inflammation in MND

Run MND NSW Research Grant
Lead investigator: Dr Jennilee Davidson
Institution: Macquarie University
Title: Characterising the interactome of sequestosome-1 (p62) – the peacemaker between protein homeostasis and dysfunction

Dr Paul Brock MND NSW Research Grant
Lead investigator: Dr Shu Yang
Institution: Macquarie University
Title: Characterising CHCHD10-mediated TDP-43 mitochondria entry in MND

MonSTaR MND Research Grant
Lead investigator: Associate Professor Mary-Louise Rogers
Institution: Flinders University
Title: Refinement of p75 ^ECD measurement as a biomarker for clinical trials for MND

Daniel Veysey MND Research Grant
Lead investigator: Dr Rosie Clark
Institution: University of Tasmania
Title: Releasing inhibitions – a novel approach to determine targets of inhibitory dysfunction in ALS

Daniel McLoone MND Research Grant
Lead investigator: Dr Fleur Garton
Institution: University of Queensland
Title: An Australian Sporadic ALS transcriptome resource

Daniel McLoone MND Research Grant
Lead investigator: Dr Rita Mejzini
Institution: Murdoch University
Title: Development of RNA-like precision therapies to reduce toxic MND protein in the neuron

Daniel McLoone MND Research Grant
Lead investigator: Associate Professor Peter Noakes
Institution: University of Queensland
Title: Stabilising neuromuscular signalling in motor neuron disease

Daniel McLoone MND Research Grant
Lead investigator: Associate Professor Sean Millard
Institution: University of Queensland
Title: Understanding how the ALS risk factor, GGNBP2, impairs a cellular process defective in many people with ALS

Jenny Simko MND Research Grant
Lead investigator: Dr Duncan Crombie
Institution: University of Melbourne
Title: Utilising stem cells derived from people with MND to create artificial ‘mini-organs’ in the search for MND therapeutics

Mavis Gallienne and Graham Lang MND Victoria Research Grant
Lead investigator: Dr Brooke-Mai Whelan
Institution: University of Queensland
Title: Save Our Speech (SOS) study

Superball XV MND Research Grant
Lead investigator: Professor Aaron Russell
Institution: Deakin University
Title: Investigating the role of neurturin (a specific protein) as a therapeutic strategy to delay ALS disease progression

Ian Sneddon Two Rivers Run MND Research Grant
Lead investigator: Professor Mark Wilson
Institution: University of Wollongong
Title: Identifying new drugs from Australian native plants and animals to treat motor neuron disease

Peter Stearne Familial MND Research Grant
Lead investigator: Dr Sonam Parakh
Institution: Macquarie University
Title: Nucleoredoxin (NRX), a novel gene therapy target against TDP-43 multifaceted pathogenic mechanisms

NTI MND Research Grant
Lead investigator: Dr John Lee
Institution: University of Queensland
Title: Therapeutic potential of targeting one of the core players of inflammation (Inflammasome) in MND

Col Bambrick MND Research Grant
Lead investigator: Dr Adam Walker
Institution: University of Queensland
Title: Finding enzymes to remove MND pathology from neurons

Murray Geale MND Research Grant
Lead investigator: Dr Derik Steyn
Institution: University of Queensland
Title: Decoding disease impact on the hypothalamus across the ALS-FTD spectrum of disease

Fat Rabbit MND Research Grant
Lead investigator: Dr Margreet Ridder
Institution: University of Queensland
Title: Drug controlled gene therapy for motor neurone disease

MNDRA PhD Scholarship Top-Up Grants (2023–2025)

Lead investigator: Elise Kellet
Institution: Queensland Brain Institute, University of Queensland
Title: The role of post-translational modification of TDP-43 in disease pathology

Lead investigator: Kathryn Maskell
Institution: University of Tasmania
Title: Do upper and lower motor neurons need different treatments to effectively stop neurodegeneration in ALS?

Lead investigator: Aida Viden
Institution: University of Melbourne
Title: Investigating the anatomical origins of MND

MND Research Australia awarded over $3.1 million to support the best MND research commencing in 2022. The suite of grants awarded at the annual grants allocation meeting on 10 November 2021 included the Betty and John Laidlaw MND Research Prize for a mid-career researcher, three postdoctoral fellowships and 17 innovator grants. MNDRA has also awarded the Scott Sullivan MND Postdoctoral Fellowship, which is largely funded by MND&ME with a contribution from MNDRA. Four PhD Scholarship Top-Up grants were awarded in early 2022.

Betty and John Laidlaw MND Research Prize (2022–23)
Lead investigator: Associate Professor Parvathi Menon
Institution: University of Sydney
Title: Improved Understanding of Brain Excitability in ALS/MND
Cortical hyperexcitability, is an important mechanism underlying MND which contributes to nerve degeneration and consequent muscle wasting, varying MND types, adverse prognosis, and disease progression. Mechanisms underlying cortical hyperexcitability in MND are partially understood and their limitation or reversal may be vital in MND management. Loss of inhibitory interneurons has been proposed as a mechanism for cortical hyperexcitability in mouse models. This research project will help prospectively interrogate the function of distinct cortical interneuron populations in sporadic MND patients using unique cortical stimulation techniques to improve understanding of this key pathogenic mechanism.

Bill Gole MND Postdoctoral Fellowship (2022–24)
Lead investigator: Dr Fiona Bright 
Institution: Macquarie University
Title: Exploring undefined regions & novel functions of the TDP-43 protein - The molecular pursuit to uncover the cause and ultimately find a cure for MND
In 95% of MND patients, abnormal protein deposits of TDP-43 are present within cells of the brain, and spinal cord. The molecular mechanisms underlying TDP-43 pathology in MND remains unknown. The structural parts of TDP-43 containing disease-causing mutations have undergone detailed studies, yet the remaining part is significantly understudied. Importantly, this part contains TDP-43’s transport and protein binding machinery with ample opportunity to learn about its physiological movement within the brain and spinal cord. Novel regulators of TDP-43 transport, and other functions awaits discovery. This project will explore undefined regions and molecular pathways of TDP-43 which holds the key to understanding what goes wrong in MND.

Beryl Bayley MND Postdoctoral Fellowship (2022–24)
Lead Investigator: Dr Mouna Haidar
Institution: Florey Institute of Neuroscience and Mental Health
Title: A novel gene therapy approach targeted to overactive brain motor neurons
There is increasing evidence that motor neurons in the brain are electrically overactive in MND, leading to damage of motor neurons in the spinal cord. We will evaluate a new gene therapy approach targeting motor neurons in the brain to reduce their overactivity in MND. Using "designer receptor" technology, we will test this approach in motor neurons grown from MND patients and mouse models. We predict that our gene therapy strategy will reduce the burden of electrical overactivity in the brain, preserving motor neurons and correcting these models, supporting future development of designer receptor therapy for MND.

Nancy Gray MND Postdoctoral Fellowship (2022–24)
Lead investigator: Dr Marnie Graco
Institution: Institute for Breathing and Sleep, VIC
Title: Optimising quality of life and survival in motor neurone disease by improving the use of overnight breathing support
Supporting breathing overnight with non-invasive ventilation improves life expectancy in motor neurone disease (MND). However only 19% of Australians living with MND currently access the treatment. This research will directly address this problem, by: 1) understanding the barriers to the uptake of non-invasive ventilation from the perspective of people living with MND, their carers / family and clinicians; 2) carefully designing a strategy that targets these barriers; and 3) implementing and testing the effectiveness of this strategy in a single Australian location. This research will optimise quality of life and survival in MND by improving the uptake of non-invasive ventilation.

Scott Sullivan MND Research Fellowship (2022–24)
Lead Investigator: Dr Fleur Garton
Institution: University of Queensland
Title: An investigation into MND biomarkers and genetic risk mechanisms to improve diagnosis/tracking and therapeutic avenues for sporadic ALS
This fellowship aims to bring together an MND research program with two key themes to address 1) new biomarkers of disease and 2) mechanisms underlying genetic risk associations. It will focus on the relatively understudied (but most common form) sporadic ALS. Potential outcomes include new methods for diagnosing and/or tracking ALS using biomarker data (alongside other biological and clinical information) and novel avenues for therapeutic intervention. By integrating clinical, molecular, and model systems and focussing on ALS cases without a known mutation (>80%), the research program will maximise the opportunity to improve the care and cure of those with MND.

Charcot Award
Lead investigator: Dr Emma Devenney
Institution: University of Sydney, NSW
Title: Harnessing Artificial Intelligence Computer Models in MND: a novel pathway to improve patient outcomes
The systems responsible for thinking and moving work together to help us complete complex tasks. These systems may become dysfunctional early in MND and can occur before the onset of physical symptoms. This project will develop objective tests, using cutting-edge technology including Artificial Intelligence models, to accurately identify and define these features. This project will also identify the earliest brain changes that cause these symptoms. Overall, this project may lead to improvements in the diagnostic process and provide markers for progression and therapeutic effect that will improve timely access to support and care and appropriate access to pharmaceutical therapies.

Col Bambrick MND Research Grant
Lead investigator: Dr Gabriel S. Trajano
Institution: Queensland University of Technology, QLD
Title: High-density electromyography as a new tool to monitor motor neurone changes in MND
There is a lack of biomarkers to monitor MND progression. Current methods to evaluate motor neurone changes have limited applicability because they are invasive, painful, and can only record few motor units. We propose the use of innovative non-invasive high-density electromyography to record the activity of motor units in MND patients. Our pilot data in MND patients suggests this method is feasible and could be used to determine changes in motor neurone excitability along disease progression in specific types of motor neurones. This project results will help to develop a new biomarker to track disease progression and inform clinical practice.

NTI MND Research Grant
Lead investigator: Dr Frederik Steyn
Institute: University of Queensland, QLD
Title: Preclinical validation of macimorelin, a ghrelin mimetic, as a treatment for amyotrophic lateral sclerosis (ALS)
Not all patients with ALS are the same, and so treatments must target a range of disease processes that are relevant across patients with ALS. We will complete critical preclinical studies to show that macimorelin, an FDA approved compound with wide-ranging biological actions, can improve disease outcome in ALS. Results from this project will provide critical preclinical evidence to facilitate the rapid repurposing of macimorelin into extensive preclinical and clinical testing as a treatment for ALS.

Run MND NSW Research Grant
Lead investigator: Dr Tanya McDonald
Institution: University of Queensland, QLD
Title: Investigating energy balance in the progression of MND
The body requires blood glucose concentrations to be tightly regulated to maintain health. This is mainly regulated by two hormones, glucagon and insulin. The actions of glucagon appear to be impaired in MND, and may promote disease progression. This study will use mouse models of MND and MND patients to investigate whether increasing glucagon signalling restore glucose homeostasis, and thereby slows disease progression. This will help determine whether targeting glucagon signalling is a viable therapeutic option to benefit people with MND.

Dr Paul Brock MND NSW Research Grant
Lead investigator: Professor Julie Atkin
Institution: Macquarie University, NSW
Title: New mechanisms exploring the relationship between aging and motor neuron disease
Age is the major risk factor for MND, and ‘senescence’ is known to drive the aging process. Surprisingly, however, little is known about how senescence contributes to MND. Using disease models, our aim is to investigate whether two major mutant proteins induce senescence in MND and whether this contributes to the spread of MND throughout various cells of the nervous system. We will also examine whether existing drugs that kill senescent cells (“senolytics”) are protective in MND. These studies may identify new disease processes in MND and lead to the use of senolytic drugs as a novel treatment strategy.

Nancy Gray MND Research Grant
Lead investigator: Dr Andrew Phipps
Institute: University of Tasmania, TAS
Title: Understanding why nerve fibres are vulnerable in MND
Axons are long processes that allow for communication between our nerve cells and muscles to enable movement. During MND, nerve cell axons breakdown, leading to loss of motor function and mortality; the mechanism of which we do not understand. In this project, we will use human nerve cells to investigate what pathways are involved in axon breakdown. By understanding why axons are vulnerable, and what pathways dysfunction during MND, we can design novel therapies to prevent axon breakdown in MND.

Nancy Gray MND Research Grant
Lead investigator: Associate Professor Mary-Louise Rogers
Institute: Flinders University, SA
Title: Uncovering a panel of urinary proteins present in people with MND that can be used to indicate stages of disease
Our laboratory are world leaders in identifying urinary molecules that are useful as readouts for clinical trials. We now propose to use high precision mass spectrometry to uncover a panel of molecules (proteins) in urine that can be used as a measure of disease at first visit to the neurologist (prognostic marker). These molecules will also be investigated to determine if they are related to traditional clinical measurements and also to disease state. We envisage producing a panel of 50 candidate molecules that can be useful to group patients with the same disease state in future clinical trials.

Nancy Gray MND Research Grant
Lead investigator: Dr Jessica Collins
Institution: University of Tasmania, TAS
Title: Developing blood tests to diagnose and monitor MND
This project aims to develop new blood tests for MND that can help us with one of the most challenging issues in the disease; distinguishing which nerve cells are degenerating, those in the brain or those that make up the nerves. These blood tests will help us monitor disease progression which will enable us to have a better understanding of the fundamental drivers of the disease. They will also help us understand the effects of new treatments and aid in more accurate and timely diagnoses and prognoses for people with MND.

Nancy Gray MND Research Grant
Lead investigator: Professor Tracey Dickson
Institution: University of Tasmania, TAS
Title: Rebalancing excitability dysfunction in MND by targeting non-neuronal cells
MND has a long pre-clinical period, with dysfunction in numerous cell types and pathways converging to cause motor neuron degeneration and loss of motor function. But what keeps this dysfunction in check for so long? In this project we turn our focus to the multifaceted process of neuronal inhibition, asking what causes it to fail and trigger the onset of ALS symptoms. To answer this critical question we will determine the role of the support cells in the brain, the glia, in the onset of inhibitory network dysfunction.

Nancy Gray MND Research Grant
Lead investigator: Dr Jeffrey Liddell
Institution: University of Melbourne, VIC
Title: How corrupted glial cells perpetrate the death of neurons
Glial cells are essential for optimal neuronal health within the central nervous system, but in MND they abandon their normal ‘neuro-supportive’ role and begin to secrete factors that cause neuronal death. We have discovered a trigger that instigates this neurotoxic conversion in MND. The work that we plan to undertake via this MNDRA Innovator Grant aims to thoroughly identify the cellular changes that occur in response to this trigger and the neurotoxic factors that the glial cells secrete. The new information generated will guide development of treatments for MND that prevent neuronal death by targeting glial cells.

Jenny Simko MND Research Grant
Lead investigator: Professor Jacqueline Wilce
Institution: Monash University, VIC
Title: Preventing toxic protein aggregation in cells by targeting stress granules
This project investigates our newly developed TIA-1 inhibitor that has potential as a neuroprotective agent against ALS. In preliminary work we have tested the TIA-1 inhibitor in vitro and also shown that it is able to modulate stress granules (SG) in cells. SGs are subcellular structures made of protein and RNA that have been shown to trigger protein aggregation as underlies neurodegenerative disease. We anticipate that TIA-1 inhibitors will modulate SG formation, preventing the formation of neurotoxic aggregate formation. The work will provide proof-of-concept for targeting TIA-1 and potentially lead to a novel mode of intervention against ALS.

Mavis Gallienne and Graham Lang MND Victoria Research Grant
Lead investigator: Associate Professor Rebekah Ahmed
Institution: University of Sydney, NSW
Title: Sleep and autonomic function across the ALS-FTD spectrum
It is recognised that the symptoms of ALS are not limited to motor weakness, but involve other major physiological changes within the body including sleep function, and pain/somatic symptoms. These changes are potentially related to changes in the autonomic nervous system and key neural structures (hypothalamus, insula and thalamus). Using novel approaches including wearable devices, and brain imaging, the prevalence of sleep and pain symptoms in ALS and FTD will be documented, the brain structures that control these changes and at what stage of the disease these changes occur to assist in early diagnosis and development of potential treatment targets.

Superball XIV MND Research Grant
Lead investigator: Professor Coral Warr
Institute: La Trobe University, VIC
Title: Developing new models to help us understand the cause of variability in MND clinical presentationAmyotrophic lateral sclerosis (ALS) shows substantial clinical heterogeneity, however what underpins this heterogeneity is not understood. In this project we will develop and use a novel in vivo animal model motor circuit, together with an established model, to test the idea that the changes in neuron excitability observed in ALS can be caused by different mechanisms, and that different changes in individual patients contribute to clinical heterogeneity. Our findings will provide important knowledge that informs future personalised treatments for ALS.

MonSTaR MND Research Grant
Lead investigator: Dr Shu Yang
Institution: Macquarie University, NSW
Title: Preclinical assessment of the therapeutic potential of CHCHD10 in the removal of insoluble protein
We recently discovered a new MND-linked mitochondrial protein CHCHD10 that is decreased in MND and FTD patient brains compared to individuals unaffected by the disease. Restoring these reduced levels of CHCHD10 in MND cell models decreased the amount of pathological protein aggregation usually seen in MND models and improved cell survival, possibly due to enhanced protein clearance pathways. Here we propose a preclinical study to assess whether increasing levels of CHCHD10 in the brains of an MND mouse model is beneficial in modifying disease onset and reducing disease severity and progression.

Peter Stearne Familial MND Research Grant
Lead investigator: Dr Lyndal Henden
Institution: Macquarie University, NSW
Title: Sex and ancestry – a recipe for gene discovery in MND
More males are affected with MND, but females have a worse prognosis. The reasons for these sex-related differences are unknown but suggest a genetic component on sex chromosomes. We aim to detect X chromosome genes that cause MND or influence disease progression by using genetic data and powerful computational tools to uncover distant ancestral relationships amongst thousands of MND cases. Integrating the largest Australian MND cohort assembled to date with global MND cases from New Zealand, United Kingdom, United States and ten European countries, this is the world’s largest MND genetics study to comprehensively investigate the X chromosome. 

Phyllis Diana Seman MND Research Grant
Lead investigator: Dr Albert Lee
Institution: Macquarie University, NSW
Title: Using proteomics to reveal the components of protein aggregates to understand MND biology and identify potential therapeutic targets
The pathological feature of MND is the presence of protein inclusions inside motor neurons – comprising mostly of the protein TDP-43. It is still not known what other protein constituents make up these protein inclusions, and their biological role(s) in causing motor neuron degeneration. We have developed a new workflow to identify what these proteins are from various stages of MND pathology. These protein ‘signatures’ enable us to map out their cellular and biological role in MND onset and progression which will help us identify new therapeutic targets and mechanisms of toxicity to prevent TDP-43 inclusion formation.

MNDRA PhD Scholarship Top-Up Grants (2022–2024)

Lead investigator: Jeryn Chang
Institution: University of Queensland
Title: Decoding the loss of appetite and pathophysiology of the brain in motor neuron disease
The loss of appetite is observed in patients with MND. This is clinically important, as energy deficits and weight loss are associated with faster disease progression and earlier death. My studies aim to identify the impact of MND on the hypothalamus, a small area of the brain that regulates appetite, and how this may contribute to functional deficits throughout the brain. Studies aim to provide a biological basis for the loss of appetite in patients with MND, which will enhance understanding of disease, and provide insights to better manage care strategies aimed at improving quality and duration of life.

Lead investigator: Sean Keating
Institution: Queensland Brain Institute, University of Queensland
Title: TDP-43 and protein clearance in the pathogenesis and treatment of MND
In MND, toxic clumps of proteins accumulate within the brain and spinal cord, leading to neurodegeneration. Using human MND tissue, neurons grown in a dish, and genetically modified MND mice, I aim to investigate how dysfunctional cellular “waste removal” systems cause protein clumping in neurons. I also aim to discover new ways to effectively stimulate these “waste removal” systems with drugs and gene therapies, and determine whether this can increase the break-down of toxic protein clumps and protect against disease. By stopping protein clumping, we aim to extend neuron survival as a therapeutic strategy to treat people living with MND. 

Lead investigator: Katherine Lewis 
Institution: University of Melbourne
Title: Characterising Myelin Changes in Motor Neuron Disease
Despite garnering much deserved attention and funding, the primary causes underlying MND onset and progression remain elusive. This, in part, may be due to most MND research being conducted with a neuroncentric focus. We know that motor neurons are encased in a lipid-rich sheath termed myelin, which is essential for neuronal health and survival. We also know that the cells that produce the myelin have been shown to exhibit MND pathology. However, the exact role of myelin-producing cells in MND remains unclear and it is unknown to what degree their dysfunction contributes to MND onset and progression. Thus, this PhD project aims to comprehensively characterise myelin changes in MND over the course of disease, using clinically relevant mouse models, complemented with sophisticated stem cell derived ‘mini brain’ model systems. By understanding the role of myelin in MND, we can provide insight into new treatment avenues and therapeutic targets to preserve motor neuron health and function.

Lead investigator: Jianina Marallag
Institution: University of Queensland
Title: The potential role of CXCR2 activation in motor neuron disease
Excessive activation of the immune system has been found to result in motor neuron death in MND. CXCR2 is a cellular receptor that is gaining interest for its involvement in recruiting immune cells to the site of injury. Inappropriate activation of this receptor may contribute to the progression of MND. This project will utilise a drug that blocks CXCR2 in mouse models of MND and patient samples to investigate if it is able to protect motor neurons by reducing immune system activity. The results will help determine if CXCR2 can be used as a therapeutic target for MND patients.

MND Research Australia awarded almost $3 million to support the best MND research commencing in 2021. The suite of grants awarded at the annual grants allocation meeting on 13 November 2020 comprises the Betty and John Laidlaw MND Research Prize for a mid-career researcher, three postdoctoral fellowships, 14 innovator grants and 8 bridge-funding grants. Two PhD Scholarship Top-Up grants were awarded in early 2021.

Betty and John Laidlaw MND Research Prize (2021–2022)
Lead investigator: Associate Professor Yazi Ke
Institution: Macquarie University 
Title: Novel therapeutic strategies targeting TDP-43 in Motor Neuron Disease

Our research team has discovered a new, previously unidentified protein complex that appears to be involved in Motor Neurone Disease (MND). This protein complex contributes to disease processes such as nerve cell death. This proposal has three main aims: firstly, to understand how different components of this protein complex contribute to its function; secondly, to study this protein complex in an established MND mouse model to understand its disease-relevance; and, finally, to harness the knowledge of this protein complex in the development of two highly feasible therapeutic approaches in a pre-clinical setting. This project could identify new therapies for MND.

Beryl Bayley MND Postdoctoral Fellowship (2021–2023)
Lead Investigator: Dr Emily McCann
Institution: Macquarie University 
Title: Investigating the role of complex genomic variation in MND

Gene mutations are the only known cause of MND, however almost 90% of patients have an unidentified genetic cause of MND. Little is also known about why the clinical presentation of MND varies substantially between patients. In this project, I will use innovative bioinformatic strategies to search through the genomes of MND patients to find complex genomic changes that play a role in the cause, onset and progression of MND. Once identified, these MND-relevant genomic changes will provide clues to how MND develops and progresses, to help patients and clinicians make informed decisions about treatment and family management strategies.

Bill Gole MND Postdoctoral Fellowship (2021–2023)
Lead investigator: Dr Thomas Shaw
Institution: University of Queensland
Title: Ultra-High Field MRI of Spinal Cord Tissue in Motor Neurone Diseases

Characterising differences in MND sub-types including ALS and PLS is important for understanding the disease. This project aims to distinguish these sub-types, which have separate patterns of brain and spine pathology. To achieve this, I will use Magnetic Resonance Imaging to measure tissue properties of brain and spine over time in MND patients, comparing these with clinical outcomes of disease. The project will generate significant outcomes by - for the first time - relating pathology in the brain and spinal cord to MND sub-types over time. This will increase understanding of mechanisms accounting for the irreversible progression of MND.

Marisa Aguis MND Postdoctoral Fellowship (2021–23)
Lead investigator: Dr Nicholas Geraghty 
Institution: University of Wollongong
Title: High-throughput flow cytometry drug screen to discover new treatments for MND

Motor Neurone Disease (MND) arises due to proteins misfolding inside motor neurone cells, leading to toxicity, cell death and loss of motor function. TDP-43 is an important protein known to misfold, leading to its clumping or “aggregating”, which causes cell death and leads to MND. This project uses a cell model in which TDP-43 forms toxic aggregates, in a high-throughput drug screen of thousands of chemicals to find potential drugs to treat MND patients. A small number of “hits” have already been identified and will be screened in animal models of MND, to identify a therapeutic to treat MND patients.

Charcot Award, funded by the NTI MND Research Grant
Lead investigator: Dr Shyuan Ngo
Institution: University of Queensland, QLD
Title: MND in space and time: deciphering the spatio-temporal landscape of cell-autonomous and non-cell-autonomous drivers of motor neuron death in MND

Motor neurons are usually supported by a number of different cells that sustain their function and survival. In MND, it is proposed that these support cells become toxic and contribute to the death of neurons, although we do not know how this occurs. Using mini 3D spinal cords that we have generated from MND patient skin cells, we will study how neurons and their support cells interact over time. This will allow us to generate the first “cell-to-cell communication network maps” that will give us insights into how we can manipulate this communication to save neurons from death.

Col Bambrick MND Research Grant
Lead investigator: Dr Robert Henderson
Institution: University of Queensland, QLD
Title: A Novel PET Imaging Marker of Astrocytes and Glutamate Reuptake in Brain and Spinal Cord in ALS

Damage to motor nerves through activation (“excitotoxicity”) is long-recognised as a potential avenue to target new therapeutics in MND. To date, there has been no reliable method to image excitotoxic injury in vivo. This novel project will test a new PET imaging method to identify key alterations in the main transporter of glutamate, the principal excitatory neurotransmitter, into glial cells in the brain and spinal cord of patients with MND. The ultimate objective is that this method will help to predict progression in individual MND patients and aid in the selection of new therapies for clinical trials.

Dr Angela Worthington MND Research Grant
Lead investigator: Dr Colin Mahoney
Institution: University of Sydney, NSW
Title: Establishing the role of high definition-density EEG in the diagnosis and monitoring of MND

There continues to be significant challenges in diagnosing and successfully treating those with motor neuron disease. We increasingly recognise that MND is a multi-systems disease, affecting structures beyond the motor systems, often in advance of weakness. It is crucial to develop sensitive tools to detect pathological changes across other brain regions. We will use high-density electroencephalography (EEG), to assess abnormal brain wave changes relating to both cognitive and motor processes, potentially in advance of motor weakness. The detection of early brain changes using this innovative technology may reduce diagnostic delay, and improve precision in prognosis and enrolment in clinical trials.

Dr Paul Brock MND NSW Research Grant
Lead investigator: Dr David McKenzie
Institution: University of Sydney, NSW
Title: Development of an amperometric biosensor for the detection of TARDNA binding protein 43 (TDP-43) in MND

The underlying causes of amyotrophic lateral sclerosis (ALS, a subtype of MND) are not yet completely understood. This complicates timely and accurate diagnosis and the development of new efficient treatments. The hallmark of ALS is a protein named TDP-43 that accumulates in degenerating motor neurons of around 95% of people with ALS. We will develop a biosensor, a device that is able to detect TDP-43 in liquids, to study in future why and how this happens and if it can be reversed. In future, our biosensor can also be modified to detect other molecules relevant for ALS or other MNDs.

Fat Rabbit MND Research Grant
Lead investigator: Dr Adam Walker
Institution: University of Queensland, QLD
Title: Defining the involvement of ubiquilin-2 in MND

The mechanisms that cause the death of motor neurons in MND are still not completely understood. In this project, we will employ cutting-edge genetic engineering technology in cells to identify genes that control the pathology formed by a key MND-related protein. Importantly, unique inherited mutations in this core pathological protein also cause MND in some Australian/New Zealand families. We will analyse the mechanisms of disease related to this protein, and compare our results to human pathology. Overall, these studies will define, in an unbiased high-throughput manner, the early pathological mechanisms involved in MND.

Jack and Joan Thompson MND Research Grant
Lead investigator: Dr Mouna Haidar
Institution: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Will reducing abnormal cortical activity in MND have a therapeutic effect?

Nerve cells in the motor regions (or motor neurons) of the brain carry signals to the spinal cord which in turn communicate with muscles to control movement. These brain motor neurons are overactive early in MND and eventually die, losing their ability to initiate and control muscle movement. We will evaluate a novel genetic approach targeted to brain motor neurons to reduce their overactivity in a mouse model of MND. Our approach uses "chemogenetic technology" to selectively reduce the overactivity of brain motor neurons. This study will encourage future use of our novel approach for the potential treatment of MND.

Jenny Simko MND Research Grant
Lead investigator: Dr Nirma Perera
Institution: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Autophagy in Neuroglia: a hidden player in abnormal MND proteostasis

MND is characterised by accumulation of toxic protein deposits in motor neurons and surrounding neuronal supporting glial cells. Autophagy is the only pathway in our cells that can purge large protein deposits. Therapeutic rescue of autophagy to clear culprit protein aggregates may have therapeutic potential. Many studies so far have focused on exploring neuronal autophagy while glia autophagy remain unexplored. Using the powerful combination of an autophagy reporter mouse model, stem cell derived glia and post-mortem tissue, we will analyse autophagy in glia for the first time, providing new insights leading to therapeutic modulation of intricate autophagy pathway in MND.

Judy Mitchell MND Research Grant
Lead investigator: Dr Victor Anggono
Institution: University of Queensland
Title: Molecular mechanisms underlying the cytoplasmic aggregation of the RNA binding protein, SFPQ, in ALS

The mislocalisation and aggregation of RNA binding proteins are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms underlying these aberrant processes are poorly understood. This project aims to define the molecular basis of zinc-induced cytoplasmic aggregation of an ALS-associated RNA binding protein, SFPQ. Using a combination of biochemistry, and structural and cell biology, this project will examine how two human SFPQ variants that are exclusively found in familial ALS subjects affect neuronal functions. The outcomes of this study will provide a novel conceptual framework for understanding the cytoplasmic aggregation of RNA binding proteins in ALS.

Mavis Gallienne and Graham Lang MND Victoria Research Grant
Lead investigator: Professor David Berlowitz
Institution: University of Melbourne
Title: REPAIR MND: REduced PAtient – ventilator asynchrony with Artificial Intelligence assisted Respiration in MND

Non-invasive ventilation (NIV), overnight breathing support with a machine and mask, is the most effective way to increase survival in MND. NIV only works if you use it and our team has shown that careful coordination of the breathing machine to the patient can convert NIV non-users into users. The coordination process is however very labour intensive and therefore challenging to translate into clinical practice. This project will build an Artificial Intelligence-based decision support tool (REPAIR MND) that will increase clinicians’ capacity to optimize NIV and usage; 20% more people with better usage is 20% more people surviving longer.

MonSTaR MND Research Grant
Lead investigator: Dr Frederik Steyn
Institution: University of Queensland, QLD
Title: Targeting NAT1 to improve metabolism and slow disease progression in MND

Through working with people with ALS we have made new discoveries on a mechanism that could contribute to more rapidly progressing disease, and impairments in metabolism that are associated with rapidly progressing disease. NAT1 is an ancient protein that controls how our mitochondria respond to metabolic stress. We have found that NAT1 is linked to metabolic imbalance and faster disease progression in people with ALS. We will now conduct a world first study to understand how NAT1 modifies the body’s response to ALS. This will help reveal how we might target NAT1 to improve outcomes in ALS.

Peter Stearne Familial MND Research Grant
Lead investigator: Professor Ian Blair
Institution: Macquarie University, NSW
Title: Genome-wide detection of short tandem repeats that are expanded in ALS

DNA mutations are responsible for familial MND and genetic factors contribute about half the risk of developing sporadic MND. However, the genetic causes of MND are unknown in one third of MND families and most genetic risk factors are unknown. Rare expansions of DNA repeat sequences cause many other neurodegenerative diseases. Until recently we had little capacity to screen MND patients for these repeated sequences. Excitingly, this is about to change: drawing on latest technologies and bioinformatics tools, this project will screen Australian MND patients in combination with international datasets to make fresh inroads to solving the genetic basis of MND.

Robert Turnbull MND Research Grant
Lead investigator: Dr Christopher Bye
Institution: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Next generation pre-clinical modelling for MND

Using a small skin sample from a person with MND, we can now grow motor neurons identical to those inside of that person’s body. This is an important breakthrough because we can use these motor neurons to find and test drugs to treat MND in that person. In this project, we have developed a new approach to grow these motor neurons inside a “living brain” to more accurately test potential treatments. We aim to show that this “living brain” model can accelerate the selection of drugs for clinical trials for people with MND.

Run MND NSW Research Grant
Lead investigator: Professor Pam McCombe
Institution: University of Queensland, QLD
Title: Revisiting excitotoxicity in ALS: how does this occur?

In MND, some of the damage to motor neurones comes about because of over-excitation. This appears to be an early event in disease. This study will examine how this occurs. We have developed novel techniques to measure amino acids that can cause over-excitation and will determine whether these are elevated in the blood of MND patients. In addition, our preliminary studies have discovered a novel molecule that helps reduce over-excitation. We will use genetic techniques to see whether variation on this molecule is associated with the clinical course of MND. This would be evidence of its involvement in MND pathogenesis.

Superball XIII MND Research Grant
Lead investigator: A/Prof Bradley Turner
Institute: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Defining upper motor neuron markers using translational RNA profiling

There is increasing evidence that MND pathology originates from the brain and spreads to the spinal cord. Yet, the molecular makeup of motor neurons in the brain is poorly understood in MND. To unravel the mechanisms behind brain dysfunction in MND, specific molecular markers or 'sign posts' of brain motor neurons are urgently needed. This project will combine next-generation genetic sequencing technology with new genetically engineered mice to define the molecular makeup of brain motor neurons for the first time. Identifying molecules that are both specific and unique to brain motor neurons will vastly accelerate research in MND, allowing us to understand the mechanisms underlying their vulnerability to degeneration in MND and highlight pathways to potential effective treatment.

MNDRA PhD Scholarship Top-Up Grants (2021–2023)

Lead investigator: Natalie Grima
Institution: Macquarie University 
Title: Investigating novel genomic and transcriptomic features of sporadic MND

MND is marked by substantial heterogeneity and it is therefore likely that personalised therapeutic strategies will be required. However, for the 90% of patients classified as having sporadic MND, the biological factors affecting development and progression remain largely unresolved. This project aims to identify novel risk and protective factors associated with sporadic MND, providing new targets for diagnosis, research and treatment. It will employ cutting-edge genomic and transcriptomic strategies to an extensive and unique collection of patient samples to look for complex genetic variants and gene expression changes associated with disease onset and/or variable development of the hallmark TDP-43 pathology.

Lead investigator: Dr Anna Ridgers
Institution: Austin Health
Title: Virtual Ventilation: An evaluation of the utility of ventilator-recorded data to titrate ventilator settings in comparison to non-invasive ventilation polysomnography

Home ventilation with non-invasive ventilation (NIV) is used to support breathing in respiratory (breathing) failure due to muscle weakness in motor neuron disease. Patients require different ventilator settings to optimally support breathing and improve symptoms and survival. Settings are based on daytime assessment, with subsequent overnight laboratory sleep study and face to face appointments. This is important for successful NIV but can be burdensome for patients and their carers. Newer generations of NIV record information that clinicians can review remotely. This study aims to assess whether remotely recorded ventilator data could be used to optimise ventilator settings without having to rely upon a hospital sleep study, providing the scientific foundation for remote, patient centred models of care.

MNDRA Linda Rynalski Bridge Funding Grants

Professor Julie Atkin, Macquarie University, NSW
Novel mechanisms of neurodegeneration induced by dysfunctional actin dynamics in MND

Dr Richard Gordon, University of Queensland, QLD     
Targeting inflammasome-driven neuropathology and motor neuron death in MND using a clinically approved cancer drug

Dr Albert Lee, Macquarie University, NSW    
Clearance of TDP-43 by PROteolysis TArgeting Chimera (PROTAC) dual targeting to treat ALS

Dr Nicole Fewings, University of Sydney, NSW    
Natural Killer cells in amyotrophic lateral sclerosis

Dr Marco Morsch, Macquarie University, NSW    
The unexplored posttranslational modification (SUMOylation) of TDP-43 affects aggregate formation and localisation

A/Prof Mary-Louise Rodgers, Flinders University, SA    
Urinary Neopterin as a candidate biomarker that can be used to test disease progress in clinical trials for Motor Neurone Disease

Dr Kara Vine, University of Wollongong, NSW    
Non-invasive drug delivery across the blood brain barrier: Improving the bioavailability of drugs for MND

Dr Trent Woodruff, University of Queensland, QLD    
Transcriptomic and Functional Evaluation of Immune-Activated Monocytes in MND

MND Research Australia has awarded almost $2.9 million to support the best MND research commencing in 2020. The suite of grants awarded at the annual grants allocation meeting on 11 October 2019 comprises the Betty Laidlaw MND Research Prize for a mid-career researcher, two postdoctoral fellowships and 20 innovator grants. 

Betty Laidlaw MND Research Prize (2020–2021)
Lead Investigator: Dr Shyuan Ngo
Institution: University of Queensland
Title: From the nucleus to the powerhouse: investigating how TDP-43- mitochondrial interactions wreak havoc in MND
In MND, the TDP-43 protein forms clumps inside neurons. While we know that these clumps of TDP-43 are toxic to the cell, we don’t know how this leads to neuronal death. We will use neurons made from human skin cells to study whether interactions between TDP-43 and mitochondria (the powerhouse of the cell) causes a breakdown in the mitochondrial network, and an inability of mitochondria to function properly, ultimately leading to the death of neurons. This will allow us to identify a key cause for the death of neurons in MND; a critical step towards developing treatments.

Bill Gole MND Postdoctoral Fellowship (2020 – 2022)
Lead Investigator: Dr Luke McAlary
Institution: University of Wollongong
Title: Targeting Prion-Like Strains of TDP-43
Toxic proteins in MND are capable of spreading from cell to cell in the spinal cord and brain by recruiting normal healthy protein. This spread is controlled by the shape of the toxic protein, some shapes spread more readily than others. Advanced imaging technologies have been produced where we can see the shape of individual proteins. We plan to use these imaging technologies to define the shape(s) of toxic MND proteins and apply a broad set of drug discovery methods to identify the best drugs to target them.

Beryl Bayley MND Postdoctoral Fellowship (2020 – 2022)
Lead Investigator: Dr Mehdi van den Bos
Institution: Westmead Hospital, NSW
Title: Deep learning as a tool to advance the diagnosis and pathophysiological understanding of ALS
ALS can be a difficult disease to diagnose and is proving even more challenging to cure. Increasingly we are realising that early intervention is needed and there are many signs brain overactivity is an early driving cause of the disease. This fellowship proposes to use advanced neurophysiological methods (probing brain function with magnetic brain stimulation and brain wave recordings) together with artificial intelligence (the technique of deep learning) to make possible early diagnosis, improve our understanding of the drivers of the disease in patients and find a reliable biological marker to accelerate drug trials that will deliver a cure.
 
Charcot Grant
Lead Investigator: Associate Professor Bradley Turner
Institution: Florey Institute of Neuroscience and Mental Health, VIC
Title: Development of a novel splice-switching molecular therapy for MND 
Mutations in the SOD1 gene are a common cause of MND. We have developed a novel therapy using powerful genetic designer drugs which target and 'turn off' the offending SOD1 gene. In this project, we will comprehensively test our therapeutic approach in motor neurons grown from MND patients and in MND mice. We predict our therapy will significantly slow down disease and protect motor neurons in MND mice due to suppression of the SOD1 gene. This will provide crucial support for continued development of our genetic therapy approach for MND.
 
Peter Stearne Familial MND Research Grant
Lead Investigator: Professor Julie Atkin 
Institution: Macquarie University, NSW
Title: Novel mechanisms of neurodegeneration induced by dysfunctional actin dynamics in MND
Actin is the most abundant protein in humans. It has many important functions, including forming the synapses that enable nerve cells to talk to each other to co-ordinate movement and brain activities. To perform these functions, actin continuously assembles and disassembles to form long filaments. Abnormalities in actin are known to be present in Alzheimer’s and Parkinson’s disease but it is unknown if they exist in MND. However we have obtained exciting new evidence that actin is also abnormal in MND. This project will examine how this occurs and whether already available drugs that regulate actin are protective in MND.
 
Jenny Simko MND Research Grant
Lead Investigator: Dr Samantha Barton 
Institution: Florey Institute of Neuroscience and Mental Health, VIC
Title: Could abnormal myelin composition be exacerbating neuronal dysfunction in MND? 
Oligodendrocytes (a type of glial cell that forms myelin) have two key roles essential for motor neuron function: to myelinate (coat) neurons and to provide sources of energy to neurons. In MND, both functions are impaired but the contribution to neuronal dysfunction remains unknown. We will comprehensively assess oligodendrocyte function in post-mortem tissue and then interrogate mechanisms of dysfunction using a highly innovative stem cell model whereby we take MND patient stem cells and turn them into mini-brain structures in the lab. Identifying the cause of altered myelination and energy production will address a gap in current knowledge and highlight the relevance of oligodendrocytes when searching for effective therapies.

Mavis Gallienne and Graham Lang MND Victoria Research Grant
Lead Investigator: Professor David Berlowitz 
Institution: Austin Health/University of Melbourne, VIC
Title: NIV@Home
Approximately 80 people with MND start non-invasive ventilation (NIV) annually in Victoria. NIV is currently established with a same-day hospital admission and then another overnight stay within two months. These admissions are burdensome and time consuming for patients, their families and carers. An ever increasing demand for inpatient beds can also delay access to NIV further increasing burden and anxiety. Once on NIV, trouble-shooting involves hospital attendance or a home visit from Outreach nursing. NIV@Home will pilot whether substituting inpatient admissions and sleep studies with home implementation and telehealth results in equivalent NIV usage but a better patient experience.

Col Bambrick MND Research Grant
Lead Investigator: Dr Richard Gordon
Institution: University of Queensland, QLD
Title: Targeting inflammasome-driven neuropathology and motor neuron death in MND using a clinically approved cancer drug
Chronic activation of the immune system and persistent inflammation in Motor Neuron Disease (MND) are considered to be key drivers of motor neuron loss. Breaking this cycle of inflammation and motor neuron death is currently considered one of the most promising treatment approaches for MND. In this study, we will test a promising FDA-approved drug which we believe can block both inflammation and death of motor neurons in MND. Most importantly, since this drug is already approved for human use, it can directly progress into clinical trials for MND if the outcomes of our research are positive.
 
MNDRA Innovator Grant
Lead Investigator: Dr Albert Lee
Institution: Macquarie University, NSW
Title: Clearance of TDP-43 by PROteolysis Targeting Chimera (PROTAC) dual targeting to treat amyotrophic lateral sclerosis (ALS) 
The pathological feature of MND is the presence of protein inclusions inside motor neurons – comprising mostly of the protein TDP-43. TDP-43 inclusions are a major contributor to disease, and therefore we are investigate ways to prevent formation and clearance of these TDP-43 inclusions. We have identified a protein that binds TDP-43 in motor neurons, and we will use this information to construct a therapeutic intervention that combines this with a new technology called PROteolysis TArgeting Chimera (PROTAC). We will perform pre-clinical evaluation of our PROTAC to specifically target and clear TDP-43 from neurons, to restore normal cellular function and health.

MNDRA Innovator Grant
Lead Investigator: Dr John Lee
Institution: University of Queensland, QLD
Title: Investigating the therapeutic inhibition of CXCR2 as a disease modifying treatment for motor neurone disease
Increased activity of our immune system can contribute to MND. One component that is gaining momentum as key driver of neuron death is CXCR2. CXCR2 is known to recruit our immune cells to site of injury. We believe that unwanted activity of CXCR2 is contributing to MND progression. This study will use a drug that will block CXCR2 in mouse models of MND, and in MND patient samples, to understand if this drug can dampen immune response and protect motor neurons. This will help determine whether targeting CXCR2 may be a viable therapeutic option to benefit people with MND.
 
Superball XI MND Research Grant
Lead Investigator: Dr Susan Mathers
Institution: Calvary Health Care Bethlehem/Monash University, VIC
Title: Identifying and responding to the health literacy needs of people living with MND/ALS – a coordinated national approach 
This project aims to understand how easy or difficult it is for people with Motor Neurone Disease (MND) to find, understand and make use of information about managing their life with the disorder. Specifically, what help do these people, together with their families or carers, need to make the decisions which are best for them? It also intends to explore how people living with MND interact with those providing information and advice on their care. Lastly the project aims to develop innovative ways of providing information and delivering health care that consumers of health services find useful and that support decision-making.
 
MNDRA Innovator Grant
Lead Investigator: Professor Pamela McCombe 
Institution: University of Queensland, QLD
Title: Possible gut derived toxins in ALS: prevalence and effects on outcome
Some of the risk of ALS is genetic and the remainder is non-genetic (environmental). In this study we will look for circulating neurotoxins in the blood of patients with ALS. This is based on preliminary studies that have already shown that some patients have elevated levels of formaldehyde and D-serine. This is significant because the source of these toxic molecules could be the gut microbiota. Some microbes, such as the Archaea could produce these toxins. This could provide a possible explanation for how gut dysbiosis could contribute to disease and provide opportunities for treatment.

MNDRA Innovator Grant
Lead Investigator: Dr Fiona McKay
Institution: University of Sydney, NSW
Title: Natural Killer cells in amyotrophic lateral sclerosis
The immune system is intimately involved in the disease process in MND and influences the rate of disease progression. This project examines a potent immune cell type called the “natural killer cell” in MND. Natural killer cells are increased in the blood in MND and found in the spinal cord in the mouse model of disease but their role in MND is unknown. We will characterise NK cells in MND patients and their relationship with disease and the inflammatory process, as well as the effects of an antiinflammatory therapy, dimethyl fumarate, on NK cells in MND.
 
MonSTaR MND Research Grant
Lead Investigator: Dr Marco Morsch 
Institution: Macquarie University, NSW
Title: The unexplored posttranslational modification (SUMOylation) of TDP43 affects aggregate formation and localisation
Aggregation of the protein called TDP-43 is a hallmark feature of ALS. The movement of TDP-43 out of the nucleus appears to be detrimental for neuron survival. For TDP-43 to localise into the right compartment, it undergoes post-translational modifications (PTMs). We recently found for the first time that one of these PTM-pathways (SUMOylation) is critical for the localisation of TDP-43 aggregates, nerve growth and cell-viability. In this proposal we aim to assess the implications of SUMOylation in vivo and in patient tissue. Importantly, the SUMOylation pathway has been recently demonstrated to be a promising therapeutic target in other neurodegenerative diseases.

Benalla Act to d'feet MND Research Grant
Lead Investigator: Associate Professor Lezanne Ooi
Institution: University of Wollongong, NSW
Title: Targeting cortical hyperexcitability and neurodegeneration in amyotrophic lateral sclerosis 
The processes that control how motor neurons communicate with one another are affected even before symptom onset in ALS. Since these changes in electrical properties are common to familial and sporadic ALS, these mechanisms are likely important in disease onset and progression. We have identified how and why these electrical properties of motor neurons change and now we will test whether preventing these changes, using pharmacological and genetic approaches, can protect motor neurons from degeneration.
 
MNDRA Innovator Grant
Lead Investigator: Dr Mary-Louise Rogers 
Institution: Flinders University of South Australia, SA
Title: Urinary Neopterin as a candidate biomarker that can be used to test disease progress in clinical trials for Motor Neurone Disease
We have identified a protein in urine of people with MND called p75ECD that can track progress of the disease. This was a significant break-through, with our laboratory being world leaders in urinary MND biomarkers. We will now examine an additional novel urinary biomarker called Neopterin, which is known to be influenced by immune status. We will determine if urinary neopterin levels in MND patients are different to healthy people useful for clinical trials to measure disease progress. Neopterin will also be compared to urinary p75ECD. The development of urinary biomarkers is critical to success of finding useful MND therapies.
 
Fat Rabbit MND Research Grant
Lead Investigator: Dr Frederik Steyn 
Institution: University of Queensland, QLD
Title: Tipping the Scales on MND: Preclinical testing of a compound with multiple actions to slow disease progression in MND
MND is a complex and variable disease, and so to treat MND, this project will advance testing of a compound that will target multiple components of disease. We will test a compound with multiple proposed biological effects; including metabolic, neuroprotective and anti-inflammatory properties. By reducing the metabolic and inflammatory effects of MND, and through protecting neurons, it is thought that this compound will slow the progression of disease and extend survival in a number of mouse models of MND. These models represent a range of MND-subtypes, including familial and sporadic forms of disease. These studies are the first step towards developing a treatment that could benefit patients across the spectrum of MND.
 
MonSTaR MND Research Grant
Lead Investigator: Dr Sicong Tu
Institution: University of Sydney, NSW
Title: Utilising multi-modal connectivity and artificial intelligence to track disease progression in ALS/MND
The absence of objective clinical markers for monitoring and predicting disease progression is a significant barrier undermining clinical care and successful clinical trial outcomes in ALS/MND. Multi-modal brain connectivity and artificial intelligence modelling are two cutting-edge techniques at the forefront of neuroscience research. This project seeks to develop these techniques in ALS/MND to advance our understanding of disease progression and develop robust and objective clinical tools for monitoring and predicting disease trajectory to improve clinical care and provide sensitive outcome measures for future therapeutic trials.
 
Run MND NSW Research Grant
Lead Investigator: Dr Kara Vine
Institution: University of Wollongong, NSW
Title: Non-invasive drug delivery across the blood brain barrier: Improving the bioavailability of drugs for MND
A problem treating Motor Neurone Disease is the blood–brain barrier (BBB). The BBB prevents the passage of certain drugs from the blood into the brain. We have designed a drug carrier that can increase the delivery of drugs into the brains of mice with MND. We will enhance this delivery further using focused ultrasound to temporarily and safely disrupt the BBB, thereby increasing drug delivery into the brain. This project will be the first validation in rodents of an ultrasound-mediated delivery strategy for MND and will allow for the immediate scale up and further testing of our novel approach. 
 
MNDRA Innovator Grant
Lead Investigator: Dr Adam Walker
Institution: University of Queensland, QLD
Title: New mouse models of TDP-43 pathology 
Most people with MND develop pathology in neurons that contains the protein TDP-43. This protein undergoes many biochemical alterations, but how this relates to disease remains unclear. This project will use newly developed virus technology to produce several different pathology-associated variants of TDP-43 in mice. This will allow us to create new mouse models that will be useful for both investigating disease mechanisms as well as testing treatments for MND.
 
NTI MND Research Grant
Lead Investigator: Associate Professor Anthony White
Institution: QIMR Berghofer Medical Research Institute, QLD
Title: Boosting microglia phagocytosis as a therapeutic approach to treat MND
Abnormal immune function in the brain has an important role in MND, but the development of new drugs to target this process has been hampered by a lack of effective model systems in which to test drugs. We have developed a new platform using human microglia (the resident immune cell of the brain) grown from blood cells of people with MND. In this project, we will use this platform to screen new and repurposed drugs for their ability to promote normal function of microglia in MND. This will greatly improve the likelihood of new drug treatments for people with MND.
 
Robert Turnbull MND Research Grant 
Lead Investigator: Dr Kelly Williams
Institution: Macquarie University, NSW
Title: Comprehensive transcriptome analysis of neuroanatomical regions with variable pTDP-43 pathology in sporadic ALS patients
Sporadic ALS cases show a hallmark pathology in the central nervous system (CNS), however the quantity and location of this pathology can vary greatly amongst cases. We aim to investigate differences in gene expression in various regions of the CNS to understand the biological mechanisms that underlie this variable pathology and why some CNS regions may be ‘protected’ from developing the pathology. We also aim to determine whether the gene expression changes are also present in patient blood samples, with the potential to be used as a disease biomarker.
 
MNDRA Innovator Grant
Lead Investigator: Associate Professor Trent Woodruff
Institution: University of Queensland, QLD
Title: Transcriptomic and Functional Evaluation of Immune-Activated Monocytes in MND
The immune system is now recognised to be different in MND. Alterations in both protective immune cells, as well as ‘disease-driving’ immune cells, can accelerate MND progression. Our research has identified an immune cell (called monocytes) and a key inflammatory protein (called C5a) that are elevated in patients with MND and linked to distinct disease presentations. This project will investigate both monocytes and C5a in healthy volunteers and MND blood, and identify alterations in genes and cell functions. This will provide important information that could help accelerate the progression of novel drugs targeting these factors.

MNDRA PhD Scholarship Top-Up Grants (2020-2022)

Lead investigator: Courtney Clark
Institution: University of Tasmania
Title: Inhibitory Regulation of Motor Neurons: A new target mechanisms for MND

Currently there are few treatments available to motor neuron disease patients, which provide substantial improvement in lifespan and quality of life. Previously therapies have focused on improving motor neuron pathology. However, in amyotrophic lateral sclerosis (ALS), inhibitory network activity which is vital for supporting motor neuron function is dysfunctional. Through the use of mouse models and induced-motor neurons, interneurons and glia derived from patient cells, this project aims to understand how inhibitory interneurons can be used as a therapy to improve motor neuron health in ALS.

Lead investigator: Laura Reale
Institution: University of Tasmania
Title: Can we stop the spread of TDP-43 pathology in ALS?

ALS is caused by a destruction of neurons that are part of the motor system in the brain and spinal cord. It is not known how disease moves through this system and we have few effective treatments to stop the spread. In my PhD, I aim to discover why one population of neurons can make another population stop working, ie, how the disease spreads, and test a non-invasive intervention to stop this destruction from spreading. If we can better understand why the whole system fails and how to protect against this, then we can develop new effective treatments for ALS.

MND Research Australia has awarded almost $4 million to support the best MND research commencing in 2019. The suite of grants awarded at the annual grants allocation meeting on 8 November 2018 comprises the Betty Laidlaw MND Research Prize for a mid-career researcher, two postdoctoral fellowships and 25 innovator grants.

Betty Laidlaw MND Research Prize 2019
Lead Investigator: Dr Marco Morsch
Institution: Macquarie University, NSW
Title: Targeting the nucleo-cytoplasmic transport machinery in sporadic and familial ALS
Mislocalisation and aggregation of TDP-43 outside of the nucleus is typical for nearly all ALS patients. Animal models have shown that this leads to death of the nerve cells that innervate the muscles and that clearance of these aggregates is beneficial. The mechanisms that drive TDP-43 out of the nucleus remain mysterious but are of immense therapeutic interest as they provide vital insight into the fundamental disease biology. This project will investigate the proteins that can modulate this mislocalisation. We will make an important contribution by uncovering the mechanisms that underpin the cause and progression of sporadic and familial ALS.

Bill Gole MND Postdoctoral Fellowship (2019 – 2021)
Lead Investigator: Dr Rosemary Clark
Institution: University of Tasmania, TAS
Title: Clinical heterogeneity in ALS: insights from interneurons?
The function of neural circuits and networks can be controlled, in part, by inhibition exerted by the interneurons. In amyotrophic lateral sclerosis (ALS), inhibitory network activities that support motor function can be altered before symptoms manifest and interneurons are implicated, however, how this relates to clinical characteristics is unclear. Through the use of novel mouse models, induced-interneurons derived from patient cells and careful examination of the ALS brain, this study will determine if specific interneuron pathology contributes to variable clinical phenotypes. This will be essential for understanding if motor alteration can be restored by improving the function of interneurons.  

Beryl Bayley MND Postdoctoral Fellowship (2019 – 2021)
Lead Investigator: Dr James Hilton
Institution: University of Melbourne, VIC 
Title: Ferroxidase dysfunction drives glial ferroptotic stress and motor neurone death via neurotoxic A1 astrocyte conversion
Proper supply and regulation of copper and iron is essential for biological functioning. Adverse impacts on these processes cause their availability to become compromised in some circumstances and accumulate to pathological levels in others. We have found this copper-iron axis is dysfunctional in the human MND central nervous system and has downstream pathological implications.  This project aims to better understand this pathway and examine how a dysfunctional copper-iron axis can lead to motor neurone death. We anticipate that elucidating the underlying mechanisms will identify new opportunities across different points of the malfunctioning pathway for developing new therapeutic interventions.
 
Charcot Grant
Lead Investigator: Professor Julian Gold
Institution: The Albion Centre, Prince of Wales Hospital, NSW Health 
Title: Phase 3 placebo controlled group sequential trial of Triumeq in patients with Motor Neurone Disease
A combination drug, Triumeq, is effective against HIV, and very safe. Surprisingly, it is even more effective against HERV-K, and importantly, Triumeq can cross into the nervous system, where it would need to work. In the Lighthouse Study, a recent small trial of Triumeq in ALS carried out in Australia, it was shown to be safe and well tolerated. Even though the study was not designed to look for benefit, the results were promising and need urgent follow up in a larger Phase 2b trial. We therefore plan to test Triumeq in ALS in a randomized, doubleblind, placebo-controlled trial in 300 patients, half to be given placebo and half active therapy, over 2 years. The study will test whether there is an improvement in the survival rate and function of people on Triumeq, and will explore whether biomarkers (blood and urine measurements of disease status) are effective for monitoring the disease. We will also measure the quality of life of people with ALS taking part in the study. Importantly, the drug company has agreed to provide Triumeq and placebo at no cost, making this trial significantly more cost effective. 
 
Neil and Norma Hill Foundation MND Research Grant
Lead Investigator: Dr Rebekah Ahmed 
Institution: University of Sydney, NSW 
Title: Physiological changes along the frontotemporal dementia amyotrophic lateral sclerosis spectrum-The hypothalamus where eating, metabolism and neurophysiology meet 
It is recognised that physiological changes including changes in eating and metabolism may modify the progression of neurodegeneration. This research aims using brain imaging and novel techniques from obesity research to examine if there are characteristic eating and metabolic changes in patients with the neurodegenerative diseases frontotemporal dementia, and amyotrophic lateral sclerosis; how these changes relate to changes in brain structure, and how they may affect disease progression and survival. This research shows the application of science to address a critical medical and social concern and offers the potential to provide novel therapeutic targets to improve survival in these devastating neurodegenerative conditions.  
 
MS WA MND Research Grant
Lead Investigator: Professor Samar Aoun
Institution: La Trobe University, VIC
Title: Best practice in end-of-life care and bereavement support:  A national survey of bereaved family carers of people with MND 
The importance of assessing and addressing the needs of family carers of people with MND during end-of-life care and into bereavement is well documented, yet little has been achieved to understand their needs and guide services to effectively meet them. This study will investigate the experiences of bereaved family carers in end-of-life care and bereavement support, through a national survey and in-depth interviews. It will provide the foundation for the implementation of targeted supports and resources for MND family carers to improve their end of life caregiving experience and contribute to decisions about early intervention to prevent the complications of grief and to develop best practice guidelines of national and international significance.
 
Gross Foundation MND Research Grant
Lead Investigator: Dr Catherine Blizzard
Institution: University of Tasmania, TAS 
Title: Can estrogen protect against synaptic disturbances in ALS?
ALS, the most common form of MND, affects males more than females. Why females have some protection against this deadly disease is not known, but this protection is lost after women reach menopause, indicating that hormones may be involved. We have preliminary data that suggests estrogen may play an important role in neuroplasticity – protecting against the synaptic deficits that occur early in ALS. We will now investigate the role that estrogen plays in synaptic plasticity in mouse models of ALS and determine if estrogen replacement is an effective therapy to prevent or slow down the symptoms of this devastating disease. 
 
MNDRA Innovator Grant
Lead Investigator: Professor Roger Chung
Institution: Macquarie University, NSW
Title: Revealing the role of protein clearance pathways in sporadic ALS
The major defining pathological hallmark of ALS is the presence of abnormal accumulation of proteins within motor neurons. These proteins are tagged with a molecule called ubiquitin. Cells label proteins with ubiquitin to mark that protein for degradation, as part of the normal “recycling” process within cells. This suggests that disruption in protein recycling may be an underlying cause of ALS. Confirming this, we have recently identified genetic mutations in one of the cell’s protein recycling pathways that cause inherited ALS. This project will examine protein profiles to identify whether this same pathway is altered in sporadic ALS patients.
 
Janette Hamilton MND Research Grant
Lead Investigator: Dr Anthony Cook
Institution: University of Tasmania, TAS
Title: Proteomic analysis of exosomes from iPS cell-derived neurons with mislocalised TDP-43
This project is about how ALS pathology spreads from one brain cell to the next.  We use human stem cells to generate brain organoids in the laboratory that are similar to human brain tissue.  We will use gene editing of stem cells to alter the TDP-43 gene to mimic pathological changes that occur in ALS.  We will then ‘spike’ organoids with these cells and measure the spread of pathology to those cells with the normal TDP-43 gene.  By replicating the progressive and neurodegenerative processes that occur in ALS, this work will provide an ideal tool to investigate new disease modifiers.
  
Jenny Barr Smith MND Research Grant
Lead Investigator: Associate Professor Peter Crouch 
Institution: University of Melbourne, VIC
Title: The neurotoxic consequences of glial iron accumulation in MND 
Although the symptoms of MND are unequivocally the result of neuronal death, there is ample evidence to implicate non-neuronal cells as the causal perpetrators.  In other words, it appears that in MND the motor neurones are being killed by other cell types.  We have recently identified a potential mechanism through which this may be happening, but confirmation of the mechanism requires further investigation. We will therefore gather additional evidence for this mechanism and piece together the sequence of events. The new information we generate will help determine the potential to treat MND by therapeutically targeting non-neuronal cells. 
  
Lady (Mary) Fairfax MND Research Grant 
Lead Investigator: Associate Professor Kay Double
Institution: University of Sydney, NSW 
Title: Validating molecular pathways of SOD1 toxicity in human ALS 
In some forms of inherited ALS the cellular protein SOD1 is abnormal, resulting in the selective death of motor nerves, which are essential for life. It is unknown how the protein is actually altered in human disease and why these changes cause the death of only these critical nerve cells. This project takes a fresh perspective, using cutting-edge analytical technologies on ALS patient samples, to understand how SOD1 protein changes contribute to the death of motor nerves. Understanding why these, but not all nerve cells, die in ALS will accelerate the development of therapies that prevent nerve cell death.
 
MNDRA Innovator Grant
Lead Investigator: Dr Michelle Farrar 
Institution: University of New South Wales, NSW
Title: Assessing preference heterogeneity with respect to MND treatment. A discrete choice experiment.
Treatment of motor neurone diseases (MND), particularly spinal muscular atrophy (SMA), is being transformed by the development and availability of novel therapies. The project will investigate the value of those therapies in terms of their clinical usefulness, costs and desirability. It brings together leading researchers in neurology, medical psychology, health economics and health services, combined with consumer and community participation, to address critical gaps in our current understanding of what motivates decisions in the treatment of MND. The project will provide much needed data to improve patient-and family-centred healthcare and inform treatment-related decision making for children and adults with MND.
 
Peter Stearne Familial MND Research Grant
Lead Investigator: Dr Jennifer Fifita 
Institution: Macquarie University, NSW 
Title: Investigating the role of large structural variation in MND by analysis of whole-genome sequencing data 
Gene mutations are the only proven cause of MND. Yet, 40% of familial MND still carry unknown gene mutations. Most genetic risk factors that underlie sporadic MND also remain to be identified. Structural changes in DNA are known to cause other neurological diseases but these changes are yet to be widely studied in MND. This project aims to identify structural and copy number variants in MND patients using cutting-edge analysis of whole-genome sequencing data. Structural and copy number variants that cause or increase risk to MND will facilitate genetic testing (including PGD in families) and provide targets for potential therapies.
 
Jenny Simko MND Research Grant
Lead Investigator: Associate Professor Nimeshan Geevasinga
Institution: Western Sydney Local Health District, NSW 
Title: Utilising novel MRI connectomic analysis to explore pathophysiological changes in ALS 
Understanding the exact pathophysiological processes underlying ALS progression remains elusive. We propose  utilising magnetic resonance imaging (MRI) based “Connectomics”, a cutting edge field in neuroimaging which conceptualises the whole brain as an interconnected network, to explore changes in patients with familial and sporadic ALS. Connectomics uses both structural and functional connectivity information to build a map of the interregional connections within the brain. We hope to integrate MRI imaging with our expertise in neurophysiological and clinical evaluation of ALS patients with a view of learning more about the progression of ALS. Understanding the degenerative process in the brain may help to target specific pathways for therapeutic purposes. 

Col Bambrick MND Research Grant
Lead Investigator: Dr John Lee 
Institution: University of Queensland, QLD 
Title: Investigating the beneficial effects of complement C3aR on immune cell glucose metabolism in MND 
In MND, activation of the immune system, C3aR, induces a protective function for our brain and spinal cord. C3aR is known to affect energy supply for immune cells to support motor neurons. We think that C3aR will protect our motor neurons by making the immune cells happy. This study will use mouse models of MND, and MND patient samples to investigate whether C3aR can provide energy and support to immune cells, which helps them to protect against MND. This will help determine whether targeting C3aR on immune cells will be a viable therapeutic option to benefit people with MND. 

Superball XI MND Research Grant
Lead Investigator: Associate Professor Seth Masters 
Institution: The Walter and Eliza Hall Institute of Medical Research, VIC
Title: Targeting cGAS/Sting to block neuroinflammation in MND  
Central nervous system accumulation of TDP-43 is a hallmark of disease in most patients suffering from MND. This has been associated with hyperinflammatory responses that precede overt symptoms of disease. We have now identified the primary innate immune pathway that triggers neuroinflammation in response to TDP-43. Our project examines this critical innate immune pathway in greater detail using models of MND and will validate a biomarker of the pathway in patient samples. Small molecule inhibitors will also be tested in model systems, which could potentially benefit those patients with MND who display elevated levels of the neuroinflammatory biomarker. 
 
Jenny Simko MND Research Grant
Lead Investigator: Professor Pamela McCombe
Institution: University of Queensland, QLD 
Title: Immunogenetics of motor neurone disease - a pilot study  
In patients with MND, there is variability in disease progression. There is also activation of the immune system. This occurs in the brain, where there is inflammation around the damaged motor neurones. There is also activation of the white blood cells and inflammatory proteins in the blood. This activation is associated with disease severity.  Because of genetic differences, people vary in their ability to activate the immune system. In this novel study we will examine genetics of the immune-related genes in MND and see whether this can be correlated with disease severity.
  
MonSTaR MND Research Grant
Lead Investigator: Dr Fiona McKay
Institution: University of Sydney, NSW
Title: Anti-inflammatory and metabolic effects of dimethyl fumarate in amyotrophic lateral sclerosis  
A clinical trial lead by Professor Steve Vucic is underway in Australia to investigate whether dimethyl fumarate (DMF), an anti-inflammatory drug used for multiple sclerosis, can slow disease progression in MND. DMF enhances activity of regulatory T cells, immune cells we have shown to be linked with slower disease progression in MND.  This project will determine the effect of DMF treatment on regulatory T cells in MND patients. In addition, we will measure in MND a newly reported effect of DMF: to skew cells towards metabolic pathways that are less inflammatory and less toxic to neurons. 
 
MNDRA Innovator Grant
Lead Investigator: Dr Parvathi Menon
Institution: Western Sydney Local Health District, NSW
Title: ALS progression: multimodal approach to assessing cortical dysfunction which may underlie pathogenesis  
This project aims to understand pathological brain processes that underlie the onset and spread of MND, the most rapidly progressive of neurodegenerative disorders. My previous studies show that cortical hyperexcitability may underlie the onset of MND and its progression. We are now using a multimodal approach to studying brain dysfunction, which includes MRI and specialised TMS-EEG techniques. This may provide earlier evidence of brain dysfunction and its progression, which may underlie clinical progression of MND. Understanding any brain abnormality underlying MND will help identify treatment, which could slow disease progression, with the ultimate aim of having a cure.  
 
Fat Rabbit MND Research Grant
Lead Investigator: Dr Sean Millard
Institution: University of Queensland, QLD 
Identifying molecular pathways affected by the sporadic ALS risk factor, GGNBP2  
The aim of our project is to identify molecular pathways that promote degeneration in sporadic ALS. Using the fruit fly model system, we will investigate how the GGNBP2 gene drives neurodegeneration in a genetic background that includes a modest number of C9orf72 repeats. We will use transcriptomics to identify changes in gene expression that occur when animals express both of these risk factors. This information is crucial for developing new therapies that target these defective pathways and could significantly improve the lives of people with sporadic ALS. 
 
MS WA MND Research Grant 
Lead Investigator: Dr Sarah Rea
Institution: The University of Western Australia, WA 
Title: Defining the interaction between p62 and TDP-43 as a potential therapeutic target for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia  
In 97% of Amyotrophic Lateral Sclerosis, TDP-43 is found in toxic cytoplasmic protein aggregates. TDP-43 is normally found in the nucleus of the cell. Another protein called p62 is found in the same aggregates. We show that expression of p62 causes TDP-43 to aggregate in the cytoplasm. p62-mediated aggregation of TDP-43 may be a critical step in disease progression. We will determine whether TDP-43 aggregation in response to cellular stresses implicated in ALS is dependent on p62. Our study will define the region of p62 that mediates TDP-43 aggregation thus identifying a target for future research into potential therapeutics. 
 
Andrew Butcher MND Research Grant
Lead Investigator: Dr Mary-­Louise Rogers
Institution: Flinders University of South Australia, SA
Title: How does Triumeq work as an MND  treatment? A study to determine the  relationship between endogenous  retrovirus, TDP43 pathology and  inflammatory signals in MND 
This  novel  project  will  determine  the  mode  of  action  of  the  anti-­retroviral  drug  Triumeq  that  is  currently   being  trialled  as  an  MND  treatment. We  ask  if  increased  endogenous  retrovirus  (ERV)  drives  TDP43   pathology  and  inflammatory  changes  in  a  feed-­back  loop  in  MND. We  will  determine  if  ERV  is  increased   in  symptomatic  TDP43  mice  and  if  Triumeq  reduces  ERV,  inflammatory  signals  and  TDP43  pathology.  We  will  also  determine  the  effect  on  lifespan  and  the  biomarker  urinary  p75ECD.  The  results from this study will  help us to understand  how  Triumeq  works, and  how endogenous  retroviruses cause MND.  
 
Benalla Act to d'feet MND Research Grant
Lead Investigator: Dr Rachel Tan
Institution: University of Sydney, NSW
Title: Prions, RNA binding proteins with prion-like domains and motor neuron degeneration   
The prion protein in its normal form (PrPC) is widely expressed in the central nervous system. Importantly, emerging evidence demonstrates that PrPC is involved in the accumulation and spread of misfolded proteins that cause neuronal death. In Motor Neuron Disease (MND), the death of motor neurons has been linked to the accumulation of proteins that bear a prion-like domain. However, the relationship between PrPC and these proteins have not been studied. This project will assess this in tissue from patients with MND, with the purpose of determining whether targeting PrPC is a viable therapeutic strategy for sporadic MND. 
 
Mavis Gallienne and Graham Lang MND Victoria Research Grant
Lead Investigator: Professor Julian Trollor
Institution: University of New South Wales, NSW 
Title: Using big data to understand the health status and service use of people with motor neurone disease 
This study uses linked data from a large sample of people with MND in NSW to describe and understand the mental health needs of people with MND, and how they use mental health services. By comparing our findings in people with MND to the those of people with other progressive neurological disorders and the NSW general population, we will understand the specific needs of people with MND. This will inform the development of specific strategies that will allow mental health services to better meet the needs of people with MND.  
 
MNDRA Innovator Grant
Lead Investigator: Dr Mehdi van den Bos 
Institution: Western Sydney Local Health District, NSW
Title: Cortigofugal dysfunction and cortical hyperexcitability in ALS – a window into ALS onset and progression utilising TMS EEG  
ALS is a devastating disease affecting much of the whole nervous system for which we have no substantive cure.  We know overactivity of the brain is directly related to how debilitating the disease is for individual patients. This project will study how overactivity arises and spreads throughout the brain through the study of brain waves. Using high resolution recordings of brain wave activity, we will track how overactivity spreads from one region of the brain to involve another causing the spread of ALS symptoms. If successful, this study would suggest we need to directly target brain overactivity to cure ALS.
 
MonSTaR MND Research Grant
Lead Investigator: Professor Mark Wilson
Institution: University of Wollongong, NSW
Title: Rapid screening of small molecule libraries to identify new drug leads to treat Motor Neurone Disease  
There are currently no effective treatments for Motor Neurone Disease (MND) - it is imperative that new treatments are identified. We have developed special motor nerve cells which show hallmark features of MND, and a powerful new drug screening technology validated as able to identify drugs that change MND pathology. Used together, these new tools provide a high throughput platform ideally suited to search for potential new MND treatments. We expect to identify small molecules that reduce features of MND in motor nerve cells. Any new effective MND treatments will be of enormous benefit to MND sufferers and their families. 
 
NTI MND Research Grant
Lead Investigator: Associate Professor Trent Woodruff
Institution: University of Queensland, QLD
Title: Manipulation of free fatty acid receptors to tame the immune response in MND 
Emerging evidence shows the immune system’s interaction with metabolic products influences neurodegenerative diseases. Our study aims to identify a role for a key immune metabolite receptor called Free Fatty Acid Receptor 2 (FFAR2) in MND. We will investigate FFAR2 expression in immune cells from MND patient blood, and examine FFAR2 in mouse MND models. We will also test whether therapeutic strategies aimed at manipulating FFAR2 activation can modify MND progression. In this way, we hope to identify a novel protective role for FFAR2 in MND, which will provide essential knowledge for future treatment strategies to slow MND progression in patients. 

Dr Paul Brock MND NSW Research Grant
Lead Investigator: Associate Professor Justin Yerbury 
Institution: University of Wollongong, NSW
Title: Is UBA1 a therapeutic target in ALS? 
A key contributing factor causing MND is dysfunctional protein recycling. Our genetic screen performed in yeast cells suggests a key enzyme in the protein recycling system modifies MND associated toxicity. This project aims to determine if this enzyme is altered in MND. We propose that this particular enzyme can repair dysfunctional protein recycling and therefore may be a therapeutic target in MND. 

NHMRC Partnership Grant
Lead Investigator: Professor Matthew Kiernan
Institution: Brain and Mind Centre, University of Sydney
Title: MND: Patient-centred care for a progressive neurological disease - evidence driving policy
The MND Research Institute of Australia (MNDRIA) is proud to be part of a consortium of research organisations, clinical groups, patient-centred organisations and care providers who have won funding from the National Health and Medical Research Council (NHMRC) to collect real-time data to inform best practice services, research and enrolment in clinical trials. The consortium was awarded an NHMRC Partnership Grant “MND: Patient-centred care for a progressive neurological disease - evidence driving policy” in April this year as part of a competitive application process. The NHMRC funding together with contributions from all stakeholders amounts to an investment of more than $2.5 million into patient-centred care over five years. MNDRIA's investment into the project will be leveraged more than four-fold. The initiative is led by MNDRIA Research Committee Chair Professor Matthew Kiernan, co-director of the Brain and Mind Centre, University of Sydney. Importantly, the project recognises people living with MND and their families as being best placed to inform policy development and service design through their lived experience of a rapidly changing condition.

Lord Mayor's Charitable Foundation – Eldon & Anne Foote Trust
Lead Investigator: Associate Professor Paul Talman
Title: Australian Motor Neurone Disease Registry
This project aims to increase the number of patients providing information to the Australian Motor Neurone Disease Registry (AMNDR) via specialist clinics nationally. The registry collates vital clinical information gathered and entered by research nurses at the specialist MND clinics in Australia. This clinical information is then used by other research in the domains of genomics, proteomics, and environmental exposures, to build comprehensive patient profiles that are essential in unlocking the pathophysiology of this incurable disease. Currently the registry is building a national information network that will link all the data on Australian MND patients in an attempt to accelerate translational research that may provide a deeper understanding of the drivers of MND and potential treatments.

MNDRA PhD Scholarship Top-Up Grants (2019 – 2021)
Lead Investigator: Megan Dubowsky
Institution: Flinders University, SA
Title: Endogenous retroviruses as a cause of motor neurone disease
Anti-retroviral treatment given to MND patients in the Lighthouse trial has suggested that endogenous retroviral expression may be a cause of MND. This PhD project aims to define a link between endogenous retrovirus and MND pathology. MND patient-derived stem cells will first be examined for evidence of endogenous retroviral activity and for the associations between TDP-43 pathology and inflammatory signals. The TDP-43 mouse model of MND will be used to determine effectiveness of antiretrovirals in decreasing the disease-associated protein, TDP-43. If successful, this project would demonstrate how endogenous retrovirus can be a potential therapeutic target for MND, through the use of antiretrovirals.

Lead Investigator: Marcus Dyer
Institution: University of Tasmania, TAS
Title: Neuronal excitability in ALS – a focus on TDP-43 mislocalisation 
In the vast majority of ALS cases, pathological movement of a protein, TDP-43, from the cell nucleus into the outer parts of the cell occurs. The pathological mechanism of how mislocalised TDP-43 causes motor neuron death is not known. This PhD project hypothesises that the presence of TDP-43 in the cytoplasm affects the activity of neurons, eventually causing their death. The project will identify if alterations in activity are one of the earliest changes as a consequence of TDP-43 misprocessing, and if we can potentially prevent this pathogenic mechanism from driving the onset and progression of ALS. 

MND Research Australia has awarded $3.31 million to support the best MND research commencing in 2018. The suite of grants comprises a Betty Laidlaw MND Research Prize, two postdoctoral fellowships and 25 grants-in-aid.

Betty Laidlaw MND Research Prize
Lead Investigator: A/Prof Justin Yerbury
Institution: University of Wollongong
Title: Proteome homeostasis dysfunction in axon terminals as a cause of MND
Motor neurons are some of the biggest cells in the human body. Some of these neurons can be up to 1 m in length. This provides a unique problem: how does a motor neuron maintain homeostasis at the synapse that is 1 m away? This project aims to characterise how motor neurons solve this unique problem and attempt to link dysfunction in synaptic homeostasis to MND by looking at proteins and genes.

Beryl Bayley MND Postdoctoral Fellowship (2018 – 2020)
Lead Investigator: Dr William Huynh
Institution: Brain and Mind Centre, University of Sydney 
Title: A multimodal approach combining novel electrophysiological and neuroimaging techniques to explore the pathophysiological mechanisms and patterns of disease spread in MND 
The project aims to determine the mechanisms underlying the development of this devastating neurodegenerative disorder and in particular, the site of disease onset. This project will result in highly significant advances in the understanding of MND pathophysiology, addressing an issue of great importance to human health given its rapidly progressive course. Importantly, the findings will result in fundamental outcomes in the understanding of MND pathogenesis by establishing cortical dysfunction as a primary pathogenic mechanism in MND. The findings will translate rapidly into clinical medicine by transforming the therapeutic approaches in MND, leading to novel therapeutic targets and cell based approaches.

Bill Gole MND Postdoctoral Fellowship (2018 – 2020)
Lead Investigator: Dr Nirma Perera
Institution: Florey Institute of Neuroscience and Mental Health    
Title: Targeting autophagy protein homeostasis pathway to improve motor neurone health in MND   
Evidence indicates that defects in protein disposal and recycling systems in nerve cells contribute to MND. Strategies that reboot protein disposal are therefore an attractive therapeutic approach. The goal of this project is to investigate the status of protein disposal pathways in MND and, use clinically-approved drugs and compounds derived from plant extracts to stimulate protein disposal pathways in MND patient-derived cell models. Lead compounds will be advanced to testing in MND mice to determine whether this approach improves disease course and pathology. If we see efficacy in these pre-clinical studies, safety of the compounds will accelerate the clinical translation.
  
Charcot Grant 
Lead Investigator: Dr Mary-Louise Rogers
Institution: Flinders University 
Title: Pre-clinical validation of growth factors delivered to motor neurons by non-viral gene therapy as a treatment for MND  
This research aims to develop an MND therapy based on delivering factors specifically to motor neurons that improve the health of the motor neurons in a pre-clinical mouse model of MND. We will also measure outcomes in the MND mice with our urinary biomarker to determine if the treatment is working. This study will inform us of the potential of this unique therapy to be developed as a valid MND treatment. Importantly giving hope to people living with MND and their families that treatments are being pursued.
 
David Flett Memorial MND Research Grant
Lead Investigator: A/Prof Julie Atkin
Institution: Macquarie University
Title: The role of a novel extracellular isoform of FUS in the pathogenesis of ALS/MND 
It is well established that after initial symptom onset, MND spreads contiguously throughout the body, and that abnormal proteins are responsible for this.  However, most proteins associated with MND are not normally found outside the cell, so how this occurs is not clear.  We have recently discovered a new protein linked to MND which is unique amongst MND-associated proteins because it exists outside the cell, implying it is quite different to the other proteins. Here we will examine the normal functions of this protein, how they become abnormal in disease, and if this protein is responsible for spreading MND.
 
MNDRA Grant-in-aid
Lead Investigator: A/Prof Mark Bellingham
Institution: University of Queensland
Title: Linking synaptic hyperexcitability to corticospinal neuron death in an animal model of motor neuron disease
Corticospinal neurons are vital for voluntary movement, but why these neurons die in MND is unknown.  MND models show increased synaptic activity during early disease, together with altered shape of corticospinal neurons and the number of synaptic connections received by these cells. Drugs acting on TrkB receptors can reduce corticospinal neuron synaptic activity in these models.  We will test whether TrkB receptor blockers can delay or prevent corticospinal neuron death.  This research will provide an important insight into the causes of corticospinal neuron death in MND, and will establish whether TrkB blockers could be a novel therapy for MND.

Superball X MND Research Grant
Lead Investigator: Prof Roger Chung
Institution: Macquarie University
Title: Evaluation of molecular biomarkers for diagnostic and prognostic use in ALS
This project will use next-generation proteomic screening technology, to simultaneously collect information on the levels of about 1000 proteins within a blood sample collected from MND patients.  This will identify a panel of proteins that are different between MND patients and healthy controls, which we believe may lead to the development of a clinical diagnostic and prognostic tool that can aid in early detection of the disease and a method for evaluating the rate of disease progression.

Jenny Simko MND Research Grant
Lead Investigator: Dr Dominic Hare
Institution: Florey Institute of Neuroscience and Mental Health
Title: The elemental signature of motor neurone disease
All life is a mixture of chemical elements. Everything cells do result from precisely balanced ratios and reactions of nearly 30 essential elements. Disease must also start as chemical reactions and disturbances of this delicate equilibrium. Using advanced technology, minuscule shifts in element ratios can be mapped and measured to determine how, when and where chemical reactions that cause MND happen. Capturing the unique ‘elemental signature’ of MND will both help understand how essential elements like copper, iron and zinc are involved in MND, and provide a new laboratory test that may detect MND years earlier than currently possible.

Peter Sterne Familial MND Research Grant
Lead Investigator: Prof Lars Ittner
Institution: University of NSW
Title: The role of TDP-43 pathology-associated astrocytosis in motor neuron disease
The brain harbors different cell types, which together orchestrate its functions. Amongst those cells are astrocytes. In MND, these astrocytes become activated as part of the inflammation of the nervous system. However, little is known about astrocytes contribute to the disease. This project will use latest genetic tools combined with established MND mouse models to decipher the role of astrocyte activation in the disease. Importantly, we will test whether controlling astrocyte activation is a new approach to treat MND. Findings from this project will significantly advance our understanding of MND and may build the basis for future therapies.
  
MonSTaR Foundation MND Research Grant 
Lead Investigator: A/Prof Anna King
Institution: University of Tasmania 
Title: Towards axon protection in ALS 
Nerve cells communicate with each other and their targets, such as muscle, via long processes called axons. In motor neuron disease these nerve cell processes degenerate and are lost, resulting in a loss of movement. Several mechanisms or axon degeneration have been recently identified, but we don’t know which of these mechanisms is involved in motor neuron disease. In this project, we will use two models to determine which mechanisms of axon degeneration are involved in nerve process loss in motor neuron disease. This will allow us to determine which molecules to target for therapeutic intervention.
  
MNDRA Grant-in-aid 
Lead Investigator: Dr Angela Laird
Institution: Macquarie University 
Title: Inducing autophagy to treat motor neuron disease 
The protein quality control pathway, autophagy, has been found to be impaired in many studies of motor neuron disease (MND). This study aims to identify drugs that can increase the function of this pathway to aid removal of toxic MND-causing proteins from neurons. Increasing the removal of these proteins will prevent formation of protein aggregates, which are one of the things known to contribute to the death of motor neurons in MND. We will perform drug testing on both cell culture and zebrafish models of MND to aid identification of drugs that can increase this protein removal and prevent signs of MND. 
  
MNDRA Grant-in-aid
Lead Investigator: Dr John Lee
Institution: University of Queensland
Title: Therapeutic testing of the clinical candidate drug PMX205 in a TDP43-based model of MND 
Immune system is a collection of processes in the body that serve to protect against disease. In MND, overactivation of the immune system leads to increased levels of C5aR1, which may lead to being harmful for the brain and spinal cord. This study will focus on validating whether blocking C5aR1 using FDA approved drug PMX205, can save nerve cells from death. This will help us determine whether targeting C5aR1 is a viable therapeutic option for slowing MND in humans. Thus, knowledge gained from this project has the potential to pave the way for future clinical trials of PMX205 in MND. 
 
Lady (Mary) Fairfax MND Research Grant
Lead Investigator: Dr Edwin (Chai) Lim
Institution: Macquarie University 
Title: Investigating cyanobacteria toxin as a causative environmental factor in pathogenesis of ALS 
Increasing global temperatures have led to an increase in blue green algae blooms, while the toxic effects of its toxin BMAA in causing MND is still unclear. We investigate how BMAA kills neurons and how it may spread from one cell to another. This will allow us to understand the mechanisms in BMAA that cause loss of function, and lead to the development of target therapy that can retain function, and stop the spread of BMAA. 
 
Fat Rabbit MND Research Grant
Lead Investigator: Prof Pamela McCombe
Institution: University of Queensland 
Title: Novel biomarkers for motor neurone disease 
There is a need for biomarkers that can measure the progression of Motor Neurone Disease, and that can be used as an endpoint in clinical trials. We have recently used mass spectroscopy to study the blood of patients with MND and have identified some new potential protein biomarkers, which show different levels in MND patients compared to controls. This project will investigate these proteins in a larger number of patients, and determine whether the levels are related to disease severity and progression.
  
MNDRA Grant-in-aid
Lead Investigator: Dr Marco Morsch
Institution: Macquarie University
Title: Microglia regulate axonal distribution and spread of TDP-43 aggregates 
Accumulation of proteins is now recognised as a common pathological hallmark of many neurodegenerative diseases. Cell-culture studies show emerging evidence for the spread of ALS aggregates and clinical observations describe a focal onset and subsequent spread of muscle-paralysis to other regions over time. This project will investigate this potential pathogenic mechanism using a living animal. Our unparalleled platform allows us to visualise and quantify the redistribution, release, and spread of these proteins. The outcomes will be the first visualisation of ALS-protein-transfer in a living animal, and provide compelling real-time evaluation of whether this represents a potential pathogenic mechanism in ALS.
 
MonSTaR Foundation MND Research Grant
Lead Investigator: Dr Shyuan Ngo
Institution: University of Queensland
Title: Using single cell RNA-sequencing of induced pluripotent stem cell derived neurones to identify novel disease mechanisms 
Our studies of energy balance in motor neurone disease (MND) show that people with MND use more energy than expected. We have new data to show that this increase in energy use might be linked to the loss of nerve cells in the spinal cord, and that it can affect patient outcome. We now aim to make nerve cells from MND patients to investigate gene signatures that might explain why nerve cells are susceptible to death and how this relates to energy balance. Insights will help to develop therapies to save nerve cells from death. 
 
MND and Me Foundation Research Grant
Lead Investigator: A/Prof Peter Noakes
Institution: Institute of Molecular Bioscience, University of Queensland 
Title: Targeting the molecular basis of muscle weakness in motor neuron disease 
Progressive muscle weakness occurs in MND.  This is caused by motor nerve endings withdrawing from muscle cells. We will investigate the mechanism that underlies the loss of nerve-muscle connections. In particular, why muscles from some MND patients respond poorly to agrin, a protein released from the motor nerve that is needed to maintain such connections We will then be testing several treatments on muscle cells from MND patients to see if we can improve their response to agrin to determine if such treatment can slow the loss of motor nerve muscle connections, thereby improving muscle strength and movement. 
 
Benalla Act to d'feet MND Research Grant
Lead Investigator: Dr Lezanne Ooi
Institution: University of Wollongong
Title: Astrocytic modulation of neuronal excitability and cell death in motor neurone disease
This project aims to understand why motor neurons are specifically vulnerable in MND. The electrical properties of motor neurons change even before symptom onset. The reasons behind this are unknown but since this is common to familial and sporadic MND, these mechanisms are likely important in disease onset and progression. We will investigate how and why the properties of motor neurons change before, during and after disease onset and the role of astrocytes, cells that normally perform a supportive role for neurons, in contributing to these changes and neuronal death in MND. Identifying these pathways may lead to a novel treatment avenue.
 
Grant McKenzie MND Research Grant
Lead Investigator: Dr Thomas Oxley
Institution: University of Melbourne
Title: Minimally invasive brain-controlled communication and navigation 
MND has the devastating consequence of limiting people’s independence and communication. Fortunately, for many, the portion of the brain responsible for movement remains intact and enables is to utilize signals to control assistive devices. However, due to invasive surgical methods, translation of existing technology has not progressed to clinical application. Our technology (STENTRODEtm) is the only existing method of extracting brain signals from within a blood vessel, which mitigates the risks associated with open-brain surgery. Having demonstrated that a Stentrode can record clinically relevant brain signals we now aim to translate this into early feasibility in a world-first human trial.
 
Mavis Gallienne and Graham Lang MND Victoria Research Grant
Lead Investigator: A/Prof Gail Robinson
Institution: University of Queensland 
Title: Longitudinal assessment of behaviour and cognition in ALS through brief Online Carers’ behavioural Questionnaire (OCQ) 
Changes in behaviour and cognitive decline are now recognised as part of the disease progression for some, but not all, ALS patients, with subtle changes, likely noticed by carers in their daily interactions. We propose to develop and validate the Carers’ Behavioural Screen as an online questionnaire. In the online format, carers can be invited to provide regular assessment of the cognitive/behavioural profile of the ALS patients in their care, even when participation in research clinics is difficult. This online screening tool could prove useful in both research and clinical care.
 
Dr Paul Brock MND NSW Research Grant 
Lead Investigator: Prof Dominic Rowe
Institution: Macquarie University
Title: Early diagnostic and staging of amyotrophic lateral sclerosis with high content image cytometry of peripheral cells 
This project uses a novel method of analysing living peripheral cells from patients with Motor Neurone Disease and control subjects.  It is able to detect the activation state of cells in the blood called monocytes that are known to be abnormal in MND. It should be able to detect the effect of new therapies that have the ability to slow the progression of MND.
 
Jenny Simko MND Research Grant
Lead Investigator: A/Prof Justin Rubio 
Institution: University of Melbourne 
Title: A precision genomics approach to dissect the pathogenesis of MND 
Genetic research has revealed important insight into the causes of MND, but there is still much to learn. We propose that the DNA genome of surviving neural cells in people who died from MND contains “hidden” information about the causes and progression of disease. To “unlock” this genomic information we have developed the means to isolate and interrogate the entire genome of single neurons from brain tissue donated for research. We expect that this research will improve understanding of MND biology and ultimately lead to the identification of new drug targets. 
 
Marie McGrath MND Research Grant
Lead Investigator: Dr Frederik Steyn
Institution: University of Queensland
Title: Investigating endocrine causes and consequence of loss of appetite in MND patients 
The inability for the body to sense and respond to changes in energy needs is of clinical concern in MND, as this may lead to energy deficit that contributes to weight loss and worsening disease outcome. In this project, we will determine how mechanisms that regulate appetite in MND are impaired. Knowledge gained from our observations will improve our understanding of widespread changes in the body and brain that occur in MND, while improving our capacity to direct therapies to improve the lives of those already living with MND.
 
MNDRA Grant-in-aid
Lead Investigator: Dr Lachlan Thompson
Institution: Florey Institute of Neuroscience and Mental Health
Title: An optimised immuno-suppression treatment for pre-clinical development of human cell based therapies for MND using rat models 
Unlike other parts of the body, the nervous system has a very poor capacity to repair itself. This means that damage, for example through the neurodegenerative process that occurs in motor neuron disease (MND), is irreversible and has permanent functional consequences for the patient. Most of the experimental therapies under development are protective strategies that aim to stop or slow the on-going disease process but do not in any way address the damage that has already occurred. This project aims to use human stem cells to generate new neurons that can one day replace those lost to the disease.
 
Lead Investigator:
Lead Investigator: Dr Bradley Turner
Institution: Florey Institute of Neuroscience and Mental Health
Title: Targeting exosome-mediated propagation of protein misfolding in MND 
One characteristic feature of MND is the progressive and systematic spread of symptoms from one region of the body to another, suggesting anatomical spread of the underlying motor neuron pathology. We recently identified a mechanism for disease protein spread in MND carried out by microscopic secretory particles called exosomes.  In this project, we will investigate whether targeting exosomes using a drug approach can slow the disease course, motor neuron loss and protein pathology in MND mice.  If supported, our study will encourage future targeting of the exosome pathway to interfere with disease protein spread to potentially slow progression of MND.
  
Col Bambrick Memorial MND Research Grant 
Lead Investigator: A/Prof Anthony White
Institution: QIMR Berghofer 
Title: Generating patient-derived microglia to investigate neuroinflammation in MND 
Our project will build important new tools for understanding the role of the immune system in MND. Inflammatory responses by resident brain and spinal cord immune cells (microglia) have an important role in MND and are key targets for therapy. Until now, research on microglia has been largely restricted to cells from animal origin. We now have new techniques to generate microglia directly from MND patients to help understand the disease and test patient-specific drugs to modulate the immune response in the brain and spinal cord. This project will provide a new approach to investigating and treating inflammation in MND.
 
Jenny Barr Smith MND Research Grant
Lead Investigator: Dr Kelly Williams
Institution: Macquarie University
Title: Seeking genomic factors that modify the progression of MND 
The only known causes of motor neuron disease are gene mutations, which account for two-thirds of hereditary MND cases in Australia. Patients who possess identical genetic mutations often exhibit different clinical characteristics. We will analyse genome sequence data from a large, well-characterised Australian MND patient cohort with known gene defects, but high variation in age of onset, progression rates and disease duration. We aim to identify new genetic modifiers that delay onset or slow progression of ALS, showing ‘resilience’ to disease. These modifiers will implicate biologically relevant functional pathways that influence disease manifestation, as potential prognostic tools and targets for therapeutic development. 

Charles and Shirley Graham MND Research Grant
Lead Investigator: A/Prof Trent Woodruff
Institution: University of Queensland
Title: Therapeutic inhibition of the terminal complement pathway as a disease-modifying treatment for MND
Activation of the immune system contributes to MND progression. We have been studying a group of immune proteins called the complement system. We have shown that blocking a specific component of complement can slow MND in mice. This grant aims to extend from this, by using an existing drug being developed for blood diseases, to block multiple components activities of complement. We hope that by repurposing this drug for MND, we can more effectively slow disease progression. If successful, we will be able to translate our findings more rapidly to human clinical trials.

In 2017, MND Research Australia awarded $3.75 million to support MND research. Two new grants were awarded this year in addition to two 3-year fellowships and 29 grants-in-aid: the Betty Laidlaw Prize for an outstanding mid-career researcher and the Charcot Grant, to be awarded annually for the highest ranking grant-in-aid.

Betty Laidlaw MND Research Prize
Lead Investigator: Dr Catherine Blizzard
Institution: University of Tasmania
Title: TDP-43 misprocessing drives synaptic deficits and ALS
Both inherited and sporadic ALS is defined by characteristic pathology of the protein TDP-43. Our research has identified a novel mechanism for how a disease associated mutation to this protein is causing degeneration of the nerve cells of the brain. We propose that the mutant protein causes a very early breakdown in communication between nerve cells. Importantly these changes occur before obvious symptoms, potentially giving significant insight into how the disease may start. We will investigate how defective function of TDP-43 alters nerve cell communication and how these changes lead to nerve cell death that characterises ALS.

Beryl Bayley MND Postdoctoral Fellowship (2017 - 2019)
Lead Investigator: Dr Emma Devenney
Institution: University of Sydney
Title: Behaviour, cognition, eye-movements and psychiatric disease in C9orf72 MND and FTD; a cross modal-approach to facilitate early and accurate diagnosis
Firstly this project will measure eye movements in patients with MND, FTD, and the C9orf72 expansion, and also asymptomatic carriers of the expansion. This will identify the exact nature of eye-movement abnormalities in these conditions and determine whether they are a feature of presymptomatic disease. Secondly, this study will address the issue of psychiatric symptoms in the same disease cohort by determining the underlying causes of these symptoms, which will inform future management strategies.

Bill Gole MND Postdoctoral Fellowship (2017 - 2019)
Lead Investigator: Dr Jennifer Fifita
Institution: Macquarie University 
Title: Investigating the molecular and pathological origins of amyotrophic lateral sclerosis
This project aims to use next-generation sequencing technologies to identify gene mutations that cause ALS, or may increase the risk of developing ALS, in patients with both familial and sporadic ALS. To understand how these new mutations cause disease, each will be studied in neuronal cell culture models, as well as in a zebrafish animal model. The identification of new ALS genes adds to DNA diagnostic testing, and provides a greater understanding of the underlying cause of ALS. New genes can be used to develop new cell and animal models, which will greatly assist in the testing and development of novel treatments for this devastating disease.

Charcot Grant
Lead Investigator: Dr Shyuan Ngo
Institution: University of Queensland
Title: Metabolic exploration in neurodegenerative disease (MEND): synergy between derangements in systemic and muscle metabolism in MND
Our current study into energy needs in MND has shown that people living with MND use more energy than expected. We also have exciting new data that shows that skeletal muscle of MND patients becomes energy hungry, and that this might cause the overall increase in energy needs in people living with MND. We now aim to further investigate the relationship between the overall energy needs of MND patients and the energy needs of their skeletal muscle. Insights gained from this study will help us develop therapies that are personalised to match the precise energy needs of individual MND patients.

MNDRA grant-in-aid
Lead Investigator: Associate Professor Julie Atkin
Institution: Macquarie University 
Title: Telomere dysfunction in ALS/MND
The risk of developing MND increases with age, but the reasons why are unclear. Most genetic forms of MND are caused by mutations in a protein called C9ORF72, and we have evidence that this damages DNA and binds to telomeres. Telomeres protect the ends of our chromosomes and they shorten with age. DNA cannot be replaced so damage to chromosomes can have serious consequences for the cell. Hence, in MND, loss or shortening of telomeres could lead to motor neurone death. We aim to characterise the telomeres in C9ORF72-MND, and determine whether telomere dysfunction triggers degeneration/death of motor neurons.

Mavis Gallienne MND Victoria Research Grant
Lead Investigator: Associate Professor David Berlowitz
Institution: Institute for Breathing and Sleep, VIC
Title: Lung Volume Recruitment in Neuromuscular Disease
As MND progresses, the inability to breathe deeply or cough effectively becomes more distressing. Breathing complications, chest infections and respiratory failure are debilitating and contribute to early death in people living with MND. “Breath-stacking” is a simple, inexpensive therapy that helps people take deep breaths. Doing this daily may stretch the chest wall, improve lung capacity, cough strength and slow the decline in breathing. This research trial is the first in the world to test whether performing these exercises regularly improves breathing function, symptoms, cough and quality of life for people living with MND over three months.

MNDRA grant-in-aid    
Lead Investigator: Dr Karin Borges 
Institution: University of Queensland
Title: Triheptanoin to improve energy metabolism in MND
Recent research indicates that problems in energy metabolism contribute to disease progression in MND. Thus alternative fuel sources are a promising approach to treat MND. Triheptanoin, the triglyceride of heptanoate (a C7 fatty acid), has already been used safely for 15 years in other disorders for energy metabolism and neuromuscular disorders. In an MND mouse model it protects against motor neurone death and delays the onset of motor symptoms. We will generate more data to show that triheptanoin targets metabolic impairments that contribute to MND. These new data will be crucial to initiate large clinical trials of triheptanoin in MND.

Mick Rodger MND Research Grant     
Lead Investigator: Dr Christopher Bye
Institution: University of Queensland
Title: Understanding disease susceptibility in idiopathic MND
Sporadic MND causes 90% of disease in patients, yet we have an extremely limited understanding of why these patients become sick, in part due to our inability to model sporadic forms of the disease. The advent of iPS stem cell technology now allows us to take cells from patients, and use them to generate genetically identical motor neurons in the laboratory. In this proposal we are using iPS cells from sporadic MND patients in a newly developed long term disease model to understand why neurons from these patients are susceptible to disease, and potentially develop new treatments.

Graham Lang Memorial MND Research Grant     
Lead Investigator: Ashley Crook
Institution: Macquarie University 
Title: Preventing motor neurone disease: barriers, facilitators, costs and benefits of genetic testing for MND in Australia
Preventing and reducing incidence of MND is only currently possible in families with a known faulty MND gene, through access to reproductive options that prevent passing on the faulty gene to future children. Little is known about how individuals from these families decide whether to have genetic counselling, have genetic testing and undergo reproductive options. We will explore what factors influence these decisions, and assess the cost-effectiveness of different genetic testing options in Australia. We will use this information to create evidence based guidelines for MND clinics and clinicians on genetic counselling and associated genetic testing options for familial MND.

MNDRA grant-in-aid    
Lead Investigator: Dr Peter Crouch
Institution: University of Melbourne
Title: Mitochondrial TDP-43
A protein known as TDP-43 is involved in the development of MND but the biological mechanisms through which it does so remain unclear. Over the past few years we have investigated if/how TDP-43 affects mitochondria – the energy-producing components that exist within all cells. We have established that TDP-43 interacts with mitochondria and, recently, an independent international team has shown that MND-causing changes to TDP-43 affect that way in which it interacts with mitochondria. The focus of our current work is to better understand the relationship between TDP-43 and mitochondria and how this relationship may contribute to the development of MND.

Jenny Simko MND Research Grant    
Lead Investigator: Professor Victoria Flood
Institution: University of Sydney
Title: The effects of active exercise combined with an enriched diet on swallowing, speech function and weight in patients with MND; a randomised trial
Eating, drinking and speaking are an important part of our life and patients with MND experience a rapid decline in these functions. Research suggests that active exercise might prolong the ability to eat and drink safely and prolong the ability to speak, however no thorough research has been conducted. Other research suggests that changes in diet might slow the progression of MND, with improved maintenance of weight status and muscle function. This study will be the first to evaluate the effects of these diet changes in patients with MND combined with active exercising on swallowing function, speech and weight status.

MNDRA grant-in-aid    
Lead Investigator: Dr Fleur Garton
Institution: University of Queensland
Title: Cell-free DNA and ALS; insight into disease mechanisms and progression
The last five years have seen rapid discovery in identifying the genes that cause ALS. Parallel investigations that improve diagnosis and patient monitoring would benefit from an objective blood-based marker of disease. In this proposal, we hypothesise that levels of cell death may increase with ALS and correlate with disease progression. We will measure cell death in ALS patients, healthy individuals, and an ALS mouse by investigating levels of circulating cell-free DNA (cfDNA). Using a cfDNA test as a biomarker for ALS presents a significant opportunity for early detection of motor neuron death and hence, rapid improvements in diagnosis.

Dr Paul Brock MND NSW Research Grant    
Lead Investigator: Dr Nimeshan Geevasinga
Institution: University of Sydney
Title: Functional and structural connectivity in ALS
MND is a progressive disorder with the underlying etiology still undetermined. Recent work has suggested cortical dysfunction, with MND and frontotemporal dementia thought to represent a disease continuum. We propose on utilising novel MRI techniques to explore changes in brain connectivity in ALS patients. Whilst there is some data on the MRI structural changes, an evolving area of neuroimaging is exploring a concept of ‘Connectomics’, looking at comprehensive maps of the human brain, then identifying which areas have increased/reduced connections in ALS patients, when compared to healthy controls. Furthermore these changes will then be correlated with novel neurophysiological biomarkers and clinical demographic scales and scores.

MNDRA grant-in-aid    
Lead Investigator: Dr Jean Giacomotto
Institution: University of Queensland
Title: New and innovative polygenic approach for understanding and modelling MNDs in zebrafish
ALS is a complex disease, lacking appropriate treatment. Although its cause appears to be multifactorial, there are strong evidences that genetics plays a role in some patients. Therefore, we believe that we can use genetics to understand this disorder and find therapeutics. Different forms of ALS exist, but they all share a common hallmark: motor neuron degeneration. We are using an innovative genetic approach in zebrafish to elucidate the individual and synergistic pathogenic role of risk-genes with the ultimate goal of generating an animal presenting motor neuron degeneration, paving the way to find therapeutics for all forms of the disease.

MNDRA grant-in-aid    
Lead Investigator: Professor Andrew Hill
Institution: La Trobe University, VIC
Title: Harnessing the power of exosomes to understand MND
The presence of aggregates of protein in the brain is characteristic of MND; however, the process by which they spread throughout the brain has eluded the MND field despite concerted efforts. We recently developed an innovative new methodology that is capable of studying protein spread in the human brain. We aim to implement this methodology in MND to discover how proteins spread from cell to cell in the diseased human brain.

Jenny Simko MND Research Grant    
Lead Investigator: Associate Professor Mark Howard
Institution: Institute for Breathing and Sleep, VIC
Title: Translation of respiratory biomarkers into MND practice
The inability to breathe is unfortunately the most common cause of death in people living with motor neurone disease. Our research group reported that breathing assistance using non-invasive ventilation (NIV) increases survival by 13 months. Importantly, respiratory muscle strength appeared to identify the best time to start NIV. We propose to use 25 years of Australian Motor Neurone Disease Register data to confirm our preliminary findings. These experiments will enable clinicians to advise individual people with MND about when breathing assistance should be started to maximise benefit and assist researchers to optimise the design of therapeutic trials in MND.

Alma Grace Holt MND Research Grant 
Lead Investigator: Dr Anna King
Institution: University of Tasmania
Title: Staying connected: determining targets to protect neuronal circuitry in ALS
Nerve cells are specialized cells which communicate with each other along long axons. MND is characterized by the nerve cells losing the ability to communicate with each other in a process called axon degeneration. Axon degeneration occurs in the motor nerve cells in the brain as well as those that control the muscles. The goal of our work it to determine the mechanisms by which axons degenerate in MND in order to find therapeutic targets to stabilise and maintain the function of these axons and their connections.

MNDRA Grant-in-aid    
Lead Investigator: Dr Albert Lee
Institution: Macquarie University
Title: Investigating the regulatory roles of Cyclin F phosphorylation in the development and prevention of ALS
Our team recently identified mutations in a new ALS/FTD gene that encodes the protein Cyclin F. It is involved in maintaining cellular health by tagging unwanted proteins (ubiquitylation) for breakdown and recycling within the cell. Mutant versions of Cyclin F, found in ALS patients, are defective in that they lack the necessary features (addition of a phosphate molecule) needed to regulate proper function, which ultimately leads to increased ubiquitylation and accumulation of proteins. This project will investigate new mechanisms of regulating Cyclin F activity that will contribute to our understanding of reducing abnormal accumulation of proteins inside motor neurons.

MNDRA Grant-in-aid    
Lead Investigator: Dr Jacqueline Leung
Institution: Wicking Dementia Research and Education Centre
Title: Identifying the role of oligodendrocytes in disease onset and progression in amyotrohpic lateral sclerosis  
In this project we will determine the role of a cell type called the oligodendrocyte in ALS. These cells produce myelin, a fatty layer surrounding the neuron processes that facilitates rapid signal transduction and provide structural support. Although oligodendrocytes appear to be affected in ALS with the presence of insoluble TDP-ˇ43 protein, in a similar way to the nerve cells, their role in ALS is unclear. In this project we will develop a mouse model with TDP-ˇ43 pathology in oligodendrocytes to determine its effects on nerve cells. This will provide evidence supporting oligodendrocytes as a potential therapeutic target in ALS.

MNDRA Grant-in-aid    
Lead Investigator: Dr Sean Millard
Institution: The University of Queensland
Title: Functional analysis of ALS candidate genes 
To effectively treat ALS, the functions of the genes involved need to be determined so that biologically relevant therapies that modulate progression of the disease can be identified. This grant will assess whether genes associated with ALS in human genome-wide association studies (GWAS) function at the neuromuscular junction (NMJ) of Drosophila melanogaster. The majority of the genes for ALS identified to date are conserved in fruit flies making this an ideal platform for assessing what these genes do. These studies will enable us to assign functions to several new ALS candidate genes, laying a foundation for future therapeutic studies.

MNDRA Grant-in-aid    
Lead Investigator: Associate Professor Greg Neely
Institution: The University of Sydney
Title: Functional genomic dissection of motor neuron disease 
There are currently there are no effective therapies for treating motor neurone disease and potential drug targets are desperately needed. Recent human genetics efforts to identify MND disease genes have been difficult, suggesting complimentary approaches may be useful. Since MND involves defects in synaptic function in motor neurons, here we will define the core synaptic machinery required for proper motor neuron function and identify synaptic targets that can suppress development of MND in vivo. These efforts will illuminate new conserved regulators of motor neuron function, information that can then be used to develop novel therapies for this devastating illness.

MNDRA Grant-in-aid    
Lead Investigator: Associate Professor Peter Noakes
Institution: The University of Queensland
Title: Targeting neuromuscular stability in motor neuron disease
Motor neurones attach to muscle cells in the body and make muscles work. Muscle weakness occurs in MND when the end of the motor neurone moves away from the muscle cell. We believe that there is a breakdown in the communication between the motor neuron and the muscle causing the neuron to withdraw. We will take muscle cells from patients with MND, place them in culture, and test them to see if they respond to chemicals normally released from motor neurons which make muscles work, and look at ways to stabilize the connection between them to improve muscle strength.

MND & Me Foundation Research Grant    
Lead Investigator: Professor David Pow
Institution: The University of Queensland
Title: Discovery of EAAT5 – a protein that may stop glutamate excitotoxicity in ALS
The cause of ALS is unclear; however, much evidence suggests that toxicity from a chemical called glutamate plays a key role. Indeed, the only therapy that improves survival in ALS acts through modulating glutamate. Therefore, finding additional mechanisms to prevent glutamate toxicity is an attractive target for the treatment of ALS. This project has a new approach to this. We have identified a new protein (EAAT5) that turns off glutamate release. It also acts as a transporter to mop up glutamate, terminating the excitatory effects. Preliminary studies showed that EAAT5 is reduced in the spinal cord of an animal ALS model. This loss of EAAT5 would cause a rise in glutamate levels and cause death of motor neurons. This study will define the anatomical and cellular distribution of EAAT5 in normal and diseased human nervous tissues, and may help identify potentially new therapeutic strategies to treat ALS.

MNDRA grant-in-aid        
Lead Investigator: Dr Mary-Louise Rogers
Institution: Flinders University, SA
Title: CSF and serum p75 extracellular domain as validation of a fluid biomarker for MND
A lack of biomarkers that can measure the effect of treatment has been identified as one of the reasons that clinical trials of treatments for MND have failed. Our group has shown a protein in urine called p75ECD is a biomarker of MND, and is the only identified so far that is a progression and prognostic marker. We now plan to validate our findings in urine by examining if serum and cerebrospinal p75ECD correlates with urinary p75ECD. This also involves collaboration with Pam Shaw’s group in Sheffield, UK. This grant will enable our marker to move forward to clinical trials.

Peter Stearne Familial MND Research Grant    
Lead Investigator: Dr  Fazel Shabanpoor
Institution: Florey Institute of Neuroscience and Mental Health, VIC
Title: Alleviation of C9orf72-mediated ALS: A novel bi-functional peptide- oligonucleotide strategy both suppressing gene expression and activating autophagic clearance of toxic protein
Abnormal expansion of the C9ORF72 gene is the most common genetic cause of MND. The product of expanded region within this gene are proteins which aggregate inside a particular group of nerve cells known as motor neurons. These toxic proteins cause the degeneration of motor neurons and progressive muscle weakness. The central objective of this study is to develop dual purpose biotherapeutic molecules known as peptide-oligonucleotides as a potential therapy for C9ORF72-linked ALS. This novel therapeutic approach prevent the formation and simultaneously clear the toxic protein aggregates.

Stanford Family MND Research Grant
Lead Investigator: Associate Professor Ronald Sluyter
Institution: University of Wollongong
Title: Establishing the therapeutic potential of the P2X7 receptor ion channel in ALS
There are currently no effective treatments for MND. Findings from our group and others indicate a role for a communication pathway (termed the ATP-P2X7 pathway) between motor neurones and other cells of the central nervous system in the progression of MND. Through the use of a new drug in a classic mouse model of MND, this project will investigate whether blockade of the ATP-P2X7 pathway can prevent MND progression. This research will provide further insight into the mechanisms in MND and assist in planning possible drug trials in people with MND.

MonSTaR Foundation MND Research Grant
Lead Investigator: Dr Rachel Tan
Institution: University of Sydney
Title: Is ATXN2 a potential therapeutic target in MND?
The death of neurones in MND is caused by a normal protein called TDP-43 becoming toxic. Cell and animal models have shown that another protein, called ataxin-2 (ATXN2), may be involved, a concept that appears more certain as genetic variability in the ATXN2 gene increases the risk of getting MND and also shortens survival. This study will assess whether variability in the ATXN2 gene impacts on protein levels (different forms of ATXN2 and toxic TDP-43) and neuronal integrity in patients with MND in order to provide critical information on whether therapeutic strategies for MND should target ATXN2.

Benalla Act to d'feet MND Research Grant
Lead Investigator: Dr Bradley Turner
Institution: Florey Institute of Neuroscience and Mental Health, VIC
Title: Profiling the gene expression pathways of motor neuron vulnerability early in development of MND
While MND typically presents in mid to late-life, the seeds for development of MND may be sown years or even decades before symptom onset. This implies the pathological processes of MND may start early in life. Using gene profiling technology, this project will identify the earliest genetic changes occurring in motor neurons in a mouse model of MND for the first time. Identification of the earliest genetic changes in motor neurons may provide new insights into potential critical players responsible for triggering motor neurone vulnerability and therefore highlight relevant gene targets and pathways for effective intervention in MND.

Stanford Family MND Research Grant
Lead Investigator: Dr Mehdi Van den Bos
Institution: University of Sydney
Title: Pathophysiological mechanisms underlying ALS: insights from novel cortical functional techniques
MND is a progressive and invariably fatal disease affecting central and peripheral parts of the nervous system, the cause and evolution of which remains incompletely understood. A growing body of evidence has provided support for a “dying forward” model of the disease and is centred on excessive excitatory activity (“glutamate excito-toxicity”) at the cortical level initiating a degenerative cascade. Whilst recent critical work at a cellular level has provided dramatic insight into this process a translational demonstration in humans is awaited. Our project will provide direct neurophysiological evidence of increased cortical excitation in humans, demonstrate how the disease spreads from this cortical excitatory origin, and is likely to provide a critical earlier biomarker by which treatment efficacy may also be judged.

MonSTaR Foundation MND Research Grant
Lead Investigator: Dr Adam Walker
Institution: Macquarie University 
Title: New proteins and pathways contributing to TDP-43-mediated neurodegeneration
In almost all patients with MND, a protein known as TDP-43 misbehaves in the brain and spinal cord. I have created genetically modified mice that develop TDP-43 pathology and disease very similar to human patients, to allow the analysis of brain and spinal cord tissues at early stages of disease development. In collaboration with other researchers, my team is using advanced biochemical analyses to narrow down the biochemical changes involved in disease in these mice. This project will characterize the role that newly identified proteins play in disease, with the goal of identifying new ways to treat MND.

Fat Rabbit MND Research Grant
Lead Investigator: Associate Professor Trent Woodruff
Institution: University of Queensland
Title: Therapeutic inhibition of HMGB1 to slow disease progression in MND
In MND there is death of nerve cells. As yet there is no way to stop these cells from dying and new approaches are thus needed. We are studying the role of the immune system in MND. We have evidence that activation of the immune system contributes to the progression of disease. In particular we have been studying a group of proteins called the toll-like receptor (TLR) system. We suggest that the therapeutic targeting of this system could slow the progression of MND. In this study we will investigate this further, using a novel therapeutic drug to treat MND mice. If this study is successful, we will then be able to perform a trial of our novel drug, which acts on this TLR pathway.

MNDRA grant-in-aid
Lead Investigator: Professor Naomi Wray
Institution: University of Queensland
Title: GWAS data for SALSA-SGC
The 2015 MNDRIA Ice Bucket Challenge Grant has provided funding to establish the Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC). The consortium has established common clinical data and biological sample collection protocols and online sample tracking systems, which are being rolled out to all major ALS clinics in Australia. This harmonised resource of patient data will underpin many future studies (including non-genomics studies). We will now take the SALSA-SGC samples forward through to scientific discovery by generation of basic genome-wide genetic data, contributing to international collaborative efforts in a paradigm proven to work in providing new leads for research.

NHMRC/MNDRA Postgraduate Scholarship (2017 - 2019)
Lead Investigator: Camille Paynter
Institution: University of Melbourne
Title: Communication, quality of life and advance care planning for people with MND and their caregiver.

MNDRA PhD Scholarship Top-up Grant
Lead Investigator: Timothy Tracey
Institution: University of Queensland
Title: Using in vitro human cortical neurons as a model to study neurometabolic defects in motor neuron disease
In MND, an inability for the body to utilise energy efficiently is believed to correlate with poorer disease outcomes. Since MND is a neurodegenerative disease, it is thought that poor energy utilisation in the nerve cells of the brain might lead to their death. By using human skin cells to make nerve cells that can be studied to see how efficiently they use energy, I will generate insights that will allow me to screen compounds that could potentially improve energy use in brain nerve cells, ultimately saving them from death.

Susie Harris Travel Fellowship
Lead Investigator: Dr Thanuja Dharmadasa
Institution: University of Sydney
Title: Motor Neurone Disease: site of origin and patterns of disease spread
MND is increasingly recognised as a complex spectrum of conditions rather than a single disease. The variable clinical presentations in MND have now led to the identification of disease ‘subtypes’, but poorly understood disease factors have limited the development of adequate therapies. This clinical study will use examination findings, nerve studies, novel imaging techniques, and genetic testing to differentiate subtypes, to better identify site of onset and patterns of disease spread. The aims of this research will be to enable earlier diagnosis, improve patient assessment and management and provide more accurate prognoses. Overall, this insight will hopefully be a platform to advance the development of new treatments.

In 2016, MND Research Australia awarded $5.07 million for a Betty Laidlaw MND Research Grant, three 3-year fellowships and 33 grants-in-aid. 

Betty Laidlaw MND Research Grant (2016 - 2018)
Lead Investigator: Dr Peter Crouch
Institution: University of Melbourne
Title: Copper malfunction in motor neurone disease: a therapeutic target for sporadic MND
We have developed the compound copper-ATSM as a treatment option for MND. Based on our outcomes from testing in animal models of MND and via our partnership with Collaborative Medicinal Development, Phase I clinical testing of the drug (for safety and tolerability) in Australian MND patients is due to start in 2016. As the initial stages of clinical testing commence, this research aims to obtain a better understanding of which drug-related processes fail in MND and when they fail relative to symptom progression. This work will generate the new information that can support further progression of copper-ATSM towards the efficacy stages of clinical testing.

Beryl Bayley MND Postdoctoral Fellowship (2016-2018)
Lead Investigator: Dr Michelle Farrar
Institution: University of New South Wales
Title: Motor neurone diseases in children and young people – understanding pathophysiology and developing treatment approaches
Motor neurone diseases in children and young people are a devastating group of disorders producing significant disability and mortality. This project will combine clinical, functional and specialised nerve assessment strategies to provide a comprehensive evaluation of pathogenesis and progression of MND in children and young people with the aim to develop and validate novel sensitive outcome measures for use in the clinical setting and trials. In addition, the project aims to accelerate clinical translation of potential therapies by further developing clinical trial readiness and assessment of health outcomes for children and young people with MND.

Bill Gole MND Postdoctoral Fellowship (2016-2018)
Lead Investigator: Dr Fleur Garton
Institution: The University of Queensland
Title: Identification of novel genetic loci and pathways associated with ALS through interrogation of multiple integrated genomics data sets
Insights into amyotrophic lateral sclerosis (ALS) have come from studies of the known mutations. However, in >85% of cases, the causative mutation of ALS is not known. In this project, we will use novel genomics and molecular methods to improve diagnosis and enhance the understanding of severe neuronal degeneration. This includes, the characterization of ALS patient neurons (derived from non-invasively collected urine cells) to fast-track genetic discovery with patient-specific treatment assays. We envisage an expanded diagnostic and treatment suite that will provide answers and options for the 85% of ALS patients for whom there is no known genetic cause.

MNDRA Postdoctoral Fellowship (2016-2018)
Lead Investigator: Dr John Lee
Institution: The University of Queensland
Title: The role of C3aR signalling in slowing down the disease progression of motor neuron disease
In MND, activation of the immune system leads to increased levels of C3aR. Although C3aR is primarily involved in immunity, it also affects energy balance and the production of nutritional factors known to support the nerve cells in the brain and spinal cord. This study will use mouse models of MND and MND patients to investigate whether C3aR can provide energy and support to save nerve cells from death. By identifying a protective role for C3aR in MND, we can determine whether targeting C3aR is a viable therapeutic option for slowing MND in humans.

Cure for MND Collaboration Initiative Grant
Lead Investigator: Professor Julian Gold   
Institution: The Albion Centre, Sydney
Title: Pilot trial of antiretroviral therapy for amyotrophic lateral sclerosis
This is a pilot clinical trial, The Lighthouse Project, to test the possibility that a virus may be the cause or trigger for motor neuron disease. The type of virus involved is actually part of our genes and therefore the therapy needs to be very specific. We will be testing an anti-retroviral drug in 30-40 patients with relatively early ALS and treating them for at least six months. There will be centres in Sydney and Melbourne and also in the U.K. This trial is an important step in trying to find the cause of MND and to contribute to our scientific understanding of this disease.

Cure for MND Collaboration Initiative Grant
Lead Investigator: Professor Gilles Guillemin     
Institution: Macquarie University
Title: New directions for early diagnosis of MND: a large-scale longitudinal analysis of multiple biomarkers to find diagnostic and prognostic “fingerprints”.
This project aims to assess the diagnostic potential of combining markers already identified by Australian and international research groups together with a large number of inflammatory molecules (in total 95 molecules out of 1 mL of serum) as biomarkers for ALS. This will help us develop better diagnostics as well as a more accurate understanding of the onset, triggers, environmental factors and progression of ALS. Moreover, we expect that identifying robust and sensitive sets of biomarkers may provide new hints for novel therapeutic strategies, or at least new directions for research on possible therapies.

Cure for MND Collaboration Initiative Grant
Lead Investigator: Dr Bradley Turner   
Institution: Florey Institute of Neuroscience and Mental Health, Melbourne
Title: A synergistic approach for treatment of MND using neurotrophic and gene therapy
MND is a complex and multifactorial disorder that is likely to require multiple agents with synergistic effects targeting different aspects of disease for effective treatment. This novel international collaborative project will examine the efficacy of a combined gene and neurotrophic therapy approach to improve motor neuron health and connections to muscle in preclinical models of MND.  Importantly, these gene and neurotrophic therapy agents can be rapidly adapted to human studies which will accelerate clinical development of this approach if supported for MND.

Jenny Barr Smith MND Collaboration Grant
Lead Investigator: Dr Peter Crouch
Institution: The University of Melbourne
Title: Drug-specific biomarkers to facilitate clinical translation of CuII(ATSM) as a potential therapeutic for MND.
Our team has developed a potential treatment option for MND and through our collaboration with a drug development company in the United States have commenced preparations to test the drug in Australian MND patients.  One aspect of these preparations is our development of an analytical technique to monitor the drug’s activity while it is being tested in people with MND.  The research we plan to undertake via funds from the Jenny Barr Smith MND Collaboration Initiative aims to establish clinical utility of this analytical technique.  This type of research is important because it can be used to guide on-going assessment of the drug when it is administered to people with MND.

Stanford Family MND Collaboration Grant 
Lead Investigator: Associate Professor Tracey Dickson     
Institution: The University of Tasmania
Title: New transgenic mouse models for determining the role of interneuron dysfunction in MND
There is considerable evidence that, in MND, motor neurons may be dying due to a toxicity that is triggered due to their over-activity – known as excitotoxcity. We have new evidence that this toxicity may initially be triggered by the death or dysfunction of another type of neuron in the brain – the interneuron. Interneurons are critical regulators of motor neuron activity and modulators of the balance that is essential for normal brain function. In this research project, we will make new transgenic mouse models that will allow us to determine if interneuron and inhibitory pathology could in fact be a central mechanism for this devastating disorder. If we are correct, translation to the development of a therapeutic would be rapid, with many modulators of inhibitory function already available for testing.

Graham Lang Memorial and Mavis Gallienne MND Research Grants
Lead Investigator: Dr Vinod Aiyappan    
Institution: Flinders University, SA
Title: A prospective study to assess the causes and treatment of sleep disordered breathing and respiratory failure in patients with motor neurone disease
Non-invasive ventilation (NIV) provides respiratory support via a mask and machine is the standard care for MND patients who develop sleep symptoms or respiratory failure. But the current NIV treatment uses standard settings in all the patients, which might result in sub-optimal treatment. This project aims to characterize the patterns of abnormal breathing in MND patients and to investigate changes in breathing abnormalities as the disease progresses. We will also test the usefulness of a new “smart” ventilator which can provide more personalised treatment (depending on the underlying breathing abnormality) in MND patients.

Cure for MND Foundation Research Grant
Lead Investigator: Associate Professor Julie Atkin
Institution: Macquarie University
Title: DNA damage and neurodegeneration in ALS/MND
Our genes are under constant attack.  Hence cells have developed systems to detect/repair DNA damage, termed the ‘DNA damage response’. However, if DNA cannot be repaired correctly following damage, permanent changes to our genetic information result that lead to motor neuron death. We have identified that damage to DNA is present in cells carrying mutations that cause most genetic forms of motor neuron disease (MND). This project will examine the detailed mechanisms by which this occurs. It will examine whether drugs that inhibit the DNA damage response are protective in cellular models of MND.

MNDRA Grant-in-aid
Lead Investigator: Dr Catherine Blizzard
Institution: The University of Tasmania
Title: Investigating synaptic dysfunction in ALS
The RNA binding protein TDP-43 is likely to play a critical role in ALS. TDP-43 is a major component of the pathology in patients with sporadic disease, and genetic mutations to this protein cause inheritable ALS. We are investigating how TDP-43 is involved in neuronal communication, acting at the synaptic connections between neurons.  We aim to determine how synaptic changes can lead to the neuronal death that happens in ALS, with the hope of pin pointing the earliest changes occurring to identify new targets for therapeutic treatment.

Cure for MND Foundation Research Grant
Lead Investigator: Professor Roger Chung    
Institution: Macquarie University
Title: New approaches to plasma biomarker studies in MND/ALS
There is an urgent need to identify a series of biomarkers that can be used to improve the speed of diagnosis, and predict more accurately prognosis and other clinical parameters in ALS.  This project will utilize a new proteomic technology to identify potential protein biomarkers in blood samples from ALS patients. We predict that these biomarkers may be useful in future for improving diagnostic and prognostic clinical evaluations.  These protein biomarkers may identify also novel biological processes associated with disease pathogenesis, and this may lead to new insight into the causes of ALS.

Cure for MND Foundation Research Grant
Lead Investigator: Dr Nicholas Cole    
Institution: Macquarie University
Title: Elucidating the pathogenesis of sporadic motor neurone disease using zebrafish models
A complete understanding of the exact cause and a cure for the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) remain elusive. The majority of ALS cases (over 90%) occur sporadically with no known genetic cause or family history. Our aim is to create an animal model that develops genuine ALS-like symptoms so that we can study these animals in the laboratory to understand the biology of the human disease and ultimately find a cure. This will be done in zebrafish, a well-established laboratory research animal for human disease research that are also suitable for the rapid testing of potential new treatments.

MNDRA Grant-in-aid
Lead Investigator: Professor Elizabeth Coulson   
Institution: The University of Queensland
Title: Regulation of neurotrophin signalling as a treatment for MND
Motor neuron disease is caused by the dysfunction and death of motor neurons, mediated by the death-signalling p75 neurotrophin receptor (p75NTR). We have developed a novel candidate therapeutic, called c29, that can inhibit p75NTR and facilitate growth factor-induced survival signalling in the SOD1 model of motor neuron disease. The aim of the current application is to alter the treatment strategy to provide c29 selectively to motor neurons to provide further proof of principle that this treatment is effective, a key step in the ongoing preclinical development of c29 as a treatment for this devastating disease.

zo-ee MND Research Grant
Lead Investigator: Dr Peter Crouch   
Institution: The University of Melbourne
Title: Proteomic investigation of functional copper deficiency in MND
Copper is an essential element needed by all forms of life, yet we have discovered that brain and spinal cord tissue collected from people who died of MND does not contain sufficient copper to sustain normal function.  In other words, the parts of the brain and spinal cord affected by MND are functionally copper deficient.  This suggests that limited availability of copper in the brain and spinal cord contributes to the development of MND.  The research we plan to undertake aims to directly address this possibility with the intention to identify new therapeutic opportunity. 

Jenny Simko MND Research Grant
Lead Investigator: Associate Professor Tracey Dickson
Institution: The University of Tasmania
Title: A systematic human pathology analysis of interneurons in MND
In preliminary studies in our laboratory we have discovered that in a subset of MND human brain cases there is a loss of a certain type of neuron known as the interneuron. Not all cases show this loss. In this investigation we will perform systematic pathological analysis in a much larger set of human post-mortem MND tissue, sourced through the Oxford Brain Bank and the Australian Brain Bank Network. This will allow us to determine which types of cases show this specific type of cell loss and importantly our experiments will determine if interneuron pathology precedes, and therefore could be a trigger for, motor neuron pathology and cell death in the brain and/or the spinal cord, causing MND.

Rosalind Nicholson MND Research Grant
Lead Investigator: Dr Archa Fox
Institution: University of Western Australia
Title: Investigating novel stress responsive structures in MND
MND/ALS is linked to toxic protein aggregates in neurons. We have found that the same proteins that aggregate in MND are also needed to form granules such as ‘paraspeckles’ when cells are stressed. The aim of this project is to investigate this useful aggregation into paraspeckles to try to understand the effects on the neurons when this process is altered in MND. Understanding which stresses are critical, and how to help motor neurons cope with the stress is an important step towards understanding what causes MND.

Peter Stearne Familial MND Research Grant
Lead Investigator: Dr Nimeshan Geevasinga
Institution: The University of Sydney
Title: Pathophysiological and diagnostic biomarkers of familial and sporadic amyotrophic lateral sclerosis
Familial forms of motor neuron disease (MND) account for around 10-15% of all cases of MND. Our goal is to study the most common form of familial ALS, secondary to the c9orf72 mutation. Our goal is to enrol carriers of this gene mutation and follow them up over time to see how their brain function changes (when measured by a unique magnetic test).  This is in addition to evaluating their overall muscle strength and functional scores. By better understanding, when and how MND may start, we can tailor treatment options more appropriately.

MonSTaR Foundation MND Research Grant
Lead Investigator: Associate Professor Robert Henderson
Institution: University of Queensland
Title: Using biomarkers to explore heterogeneity of MND
This project will continue important work examining biomarkers in MND. There is a critical need for reliable biomarkers to assess disease progression and potentially for use in treatment trials. Over the last few years we have been examining blood biomarkers and in particular neurofilaments. In this project, we will categorise those with MND according to genotype, whether or not there is cognitive impairment and rate of survival, and will compare our blood biomarkers in the different groups. We will determine whether the blood biomarkers can be used to distinguish the groups. We hope that will also allow us to provide insight into mechanisms.

MNDRA Grant-in-aid
Lead Investigator: Dr Albert Lee
Institution: Macquarie University
Title: Identifying mechanisms responsible for ubiquitination of TAR DNA-binding protein 43 (TDP-43) in ALS pathogenesis
The major hallmark of almost all ALS cases is the presence of aggregates of a particular protein (TAR DNA-binding protein 43 (TDP-43. Only a small percentage of these clinical cases bear mutations in the TDP-43 gene, with most representing sporadic disease origins. Our team has recently identified new mutations in a gene that encodes a protein that is directly involved in protein recycling in motor neurons. This project will use a series of experimental techniques to precisely identify the mechanisms by which this novel ALS protein may affect TDP-43 inclusions and map signalling pathways that are impaired in motor neurons.

MNDRA Grant-in-aid
Lead Investigator: Dr Michael Lee
Institution: The University of Sydney
Title: Dissecting the mechanisms underlying muscle fatigue in ALS using acute and cumulative resistance exercise
Fatigue is a common complaint among people with ALS. It can negatively impact on physical activity, leading to sedentary behaviour and disuse atrophy. A better understanding of the mechanism underlying fatigue has significant clinical implications for the management of ALS. In this study, we will examine the effects of exercise-induced fatigue on intracortical inhibition using established transcranial magnetic stimulation (TMS) techniques. Different types fatiguing exercises have been shown to have differential modulatory effects on intracortical inhibition in healthy subjects; however, it is unknown whether they have similar effects in ALS patients. Our study will help to clarify this important issue.

Cure for MND Foundation Research Grant
Lead Investigator: Associate Professor Guillaume Lessene
Institution: The Walter & Eliza Hall Institute of Medical Research, VIC
Title: Novel agents to prevent neuronal apoptosis in motor neuron disease
MND is characterised by “apoptosis”, a cellular process leading to the death of neurons under physiological stress. Recent advances in understanding how apoptosis works have allowed the development of new drugs that stops neuronal cell death and the progression of MND. Using our expertise in apoptosis and drug development, we identified the first pharmacological inhibitors of apoptosis. Extending from these studies, we hope to develop new drugs that will provide the basis for clinical trials in MND patients. Our goal is to slow or stop the progression of MND by harnessing the therapeutic potential of apoptosis inhibition.

Cure for MND Foundation Research Grant
Lead Investigator: Dr Marco Morsch
Institution: Macquarie University
Title: Does the transfer of ALS protein aggregates between motor neurons trigger neurodegeneration?
The accumulation of proteins in neurons and glia is a pathological hallmark of many neurodegenerative diseases. Clinical data from MND patients describes a focal onset and the subsequent spread of muscle paralysis to other regions.   This project aims to understand how ALS proteins can transfer from one cell to the next. Our team has established a zebrafish model where we can track the release and spread of ALS-proteins. The outcome of this study will be the first visualisation of ALS-protein transfer in a living animal, and provide greater understanding of whether this represents a potential pathogenic mechanism in ALS.

MNDRA Grant-in-aid
Lead Investigator: Associate Professor Greg Neely
Institution: The University of Sydney
Title: Conserved regulators of synaptic transmission and MND
Recent efforts to pinpoint the genetic causes of MND have been difficult for the vast majority of cases, suggesting complimentary approaches are required. Since MND involves defects in nerve transmission, we have combined human genomic data with systematic assessment of motor neuron function to identify 99 new genes that are require for motor neuron transmission in a live animal. Many of these genes can be considered as novel therapeutic targets for MND, and here we continue our efforts to discover and understand genes that can cause or prevent loss of motor neurons. 

Cure for MND Foundation Research Grant
Lead Investigator: Associate Professor Peter Noakes
Institution: The University of Queensland
Title: Exploiting the opposing actions of complement receptors C3aR and C5aR1 in the treatment of MND
One major part of the immune system is the complement cascade of which C3 and C5 are the key proteins. C3 is broken down into C3a and C3b, and likewise C5 is broken down to C5a and C5b. C3a and C5a activate their receptors C3aR and C5aR1 to produce opposing actions. In the nervous system, C3aR activation can protect nerve cells from death, while C5aR1 activation can drive nerve cell death. We will exploit these two opposing actions of C3aR and C5aR1 to enhance the neuro-protective actions of C3aR within the brain-spinal cord, while at the same time block with our drug the neuro-destructive actions of C5aR1, in animal models of MND. 

MND Ice Bucket Challenge Grant
Lead Investigator: Dr Susanna Park
Institution: The University of Sydney
Title: In vivo markers of ALS disease activity – linking structure to function
There remains no sensitive method to diagnose ALS or to determine how quickly the disease will progress. Our study will undertake a longitudinal study of ALS patients using neuroimaging (FDG-PET) and neurophysiological (threshold tracking TMS) tools to determine long term utility in the clinic. FDG-PET is an imaging technique which can examine changes in brain energy use in real time while threshold tracking TMS can determine the excitability level of the brain. Together these techniques provide a powerful and cutting edge assessment of current brain function - important to identify changes associated with disease progression in ALS.

Cure for MND Foundation Research Grant
Lead Investigator: Associate Professor Kenneth Rodgers 
Institution: University of Technology Sydney
Title: Identification of environmental risk factors for sporadic motor neurone disease in Australia
Toxins such as heavy metals, pesticides, fertilisers and exposure to algal blooms have been implicated as causes of sporadic MND (sMND). Long-term exposure to neurotoxins can give rise to clusters or ‘hot-spots’ of sMND. We will map sMND patients in NSW to identify any geographical clusters of sMND. We will then look for neurotoxins in plasma, hair and in the local environment to identify which toxins increase the risk of developing sMND. Limiting exposure to environmental neurotoxins could result in a gradual decline in the incidence of sMND and protect future generations of Australians.

Cure for MND Foundation Research Grant
Lead Investigator: Dr Mary-Louise Rogers
Institution: Flinders University. SA
Title: Development of novel immunogenes to improve growth factor support for motor neurons
Lack of growth factor support is one reason motor neurons die in MND. Animal studies have demonstrated the potential of glial cell-derived neurotrophic factor (GDNF), and hepatocyte growth factor (HGF) for MND. We have developed a technology called immunogenes that enable delivery of therapeutic genes into the nerves affected in MND from the circulation. This project will test immunogenes in newborn mice to determine dosing for delivery of GDNF and HGF for future treatments of mice living with MND. Data from this project will answer questions about efficacy of neurotrophic therapy with immunogenes for people living with MND.

Neale Daniher MND Research Grant
Lead Investigator: Dr Darren Saunders
Institution: University of New South Wales
Title: Ubiquitin depletion as a cause of ALS
We have identified the ubiquitin system - the cellular recycling and garbage removal system - as a novel therapeutic target for the treatment of MND. A hallmark of MND pathology is the accumulation of aggregates of ubiquitin-tagged proteins within motor neurons. We propose that disrupted ubiquitin balance (leading to cell death) is an underlying cause of MND. We will use stem cell models and transgenic animals to test a novel approach to increasing ubiquitin availability in motor neurons. This will result in a fundamental shift in our understanding of MND pathogenesis, and provide pre-clinical validation of a novel therapeutic target.

Mick Rodger & Benalla Act to d'feet MND Research Grant
Lead Investigator: Dr Sandy Shultz
Institution: The University of Melbourne
Title: Treatment with GSK2606414 in mouse models of motor neurone disease and traumatic brain injury
Traumatic brain injury (TBI) has been suggested to increase the risk of motor neuron disease (MND). We found that TBI in rodents causes progressive and degenerative changes - including TDP-43 pathologies - consistent with those occurring in MND, which supports the notion that TBI may be a causal link to MND. A new drug, GSK2606414, mitigates the neurotoxic effects of TDP-43 pathologies. Here we will investigate GSK2606414 treatment in mouse models of MND and/or TBI. These studies will increase our understanding of the causes and mechanisms of MND and TBI, and may identify a novel treatment for these devastating conditions.

Cunningham Family MND Research Grant
Lead Investigator: Dr Frederik Steyn
Institution: The University of Queensland
Title: Metabolic and gut dynamics in MND: Identifying novel strategies to meet energy needs in patients
Energy needs of people living with MND change as their symptoms worsen. We found that the ability of the gut to respond to a meal may be impaired in MND, and thus MND patients may be unable to meet their changing energy needs through diet alone. As part of a larger program, we will investigate the impact of MND, and consequential changes in dietary intake on gut bacteria. Bacteria in our gut help us absorb and regulate energy use. Thus, this project will investigate gut bacteria as a possible future target to slow disease progression through modifying energy use and availability.

Cure for MND Foundation Research Grant
Lead Investigator: Dr Lachlan Thompson
Institution: Florey Institute for Neuroscience and Mental Health, Melbourne
Title: Towards cell-based therapies for MND: identifying and tackling practical challenges in pre-clinical research
Our laboratory is interested in the idea that stem cells can be used to grow new neurons that can functionally replace those lost in neurodegenerative conditions, such as MND. We have all been hearing for a long time now about the promise of stem cells as treatment option for patients with brain and spinal cord injury. So why aren’t we there yet? This project is aimed at addressing the practical challenges in translating stem cell therapies to the clinical, particularly the need for immune suppression that allows for survival of the stem cell grafts, but without accelerating disease progression.

Cure for MND Foundation Research Grant
Lead Investigator: Dr Adam Walker
Institution: Macquarie University
Title: Pre-clinical therapeutic testing and biochemical changes associated with neuron survival in a validated TDP-43 mouse model of MND
A major hurdle in understanding what causes MND and in developing treatments has been the lack of reliable MND animal models. Recently at the University of Pennsylvania, Dr Walker characterised new genetically modified mice that for the first time develop brain and spinal cord pathology along with progressive movement deficits similar to >97% of MND patients. This project will establish these mice in Australia for pre-clinical testing of potential MND therapies, and will investigate the biochemical changes that cause neurodegeneration in the early stages of MND with the aim of identifying new therapeutic targets.

MNDRA Grant-in-aid
Lead Investigator: Dr Kelly Williams
Institution: Macquarie University
Title: Identification of phenotypic modifiers in sporadic ALS through systems genomics
Sporadic ALS comprises the vast majority of all ALS cases, however little is known about the underlying cause. There is compelling evidence for a genetic contribution, yet we observe significant variation in terms of patient age and site of onset, disease progression, prognosis and response to treatment, suggesting the existence of molecular modifiers acting to control how ALS manifests. These molecular modifiers include genetic variation (DNA genotype), physical changes to DNA (DNA methylation), and expression of genes (RNA expression). We will investigate how these molecular modifiers correspond with, or influence one another and whether they are playing a causal role in sporadic ALS. 

MNDRA Grant-in-aid
Lead Investigator: Dr Shu Yang
Institution: Macquarie University
Title: Ubiquitin Proteasome System dysfunction as a biomarker for the diagnosis and prognosis of MND
The existing tools for diagnosing and monitoring MND disease progression are poor. The aim of this study is to investigate the possibility of using MND patients’ fibroblast cells as a platform to facilitate diagnosis and prognosis. Through a cell-based assay, we found that protein degradation was inefficient in MND patients’ cells as in unaffected individuals. We are now examining protein degradation in a larger cohort of MND patients’ fibroblasts and also looking for changes with disease progression in these cells. This will serve as a pilot study for the development of a new rapid diagnostic tool, which may be translated for further testing in MND clinics.

Cunningham Family MND Research Grant
Lead Investigator: Dr Justin Yerbury
Institution: University of Wollongong
Title: Development of a biocompatible functionalised liposome drug delivery system to increase efficiency of delivery to motor neurons
Currently there is no effective therapy for the treatment of MND. One of the main hurdles to the development of new drugs is achieving an efficient delivery of the drugs to the location in the brain and spinal cord where it is required. Our objective is to develop a therapeutic delivery system that will increase the success rate of targeting any drug to motor neurons in the brain and spinal cord. This will have a major impact on the types of drugs that can be delivered to motor neurons, opening up many new potential avenues of therapy for MND.

NHMRC/MNDRA Co-funded Postgraduate Award (2016 - 2017)
Lead Investigator: Dr Nidhi Garg
Institution: University of Sydney
Title: Clinical phenotypes and novel neurophysiological and immunological biomarkers in inflammatory neuropathy
The aim of the project is to gain a better understanding of inflammatory and degenerative neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and motor neurone disease (MND). At times it can be difficult to differentiate immune-mediated motor neuropathies from MND. The identification of specific antibody markers and neurophysiological parameters will aid in diagnosis of inflammatory neuropathies and differentiation from motor degenerative disorders such as MND. While we have treatment available for the inflammatory neuropathies (such as intravenous immunoglobulin or IVIg), no such treatment is yet available for patients with MND. Identification of novel biomarkers will allow for more accurate diagnosis, prognostication and better treatment planning for patients.

MNDRA PhD Top-up Grant (2016 - 2018)
Lead Investigator: Dr Thanuja Dharmadasa
Institution: University of Sydney
Title: Motor Neurone Disease: site of origin and patterns of disease spread
Motor neurone disorders (MND) are one of the most rapidly-progressive age-related diseases known to man. However, the poorly understood disease factors limit the development of adequate treatments. This clinical study will use examination findings, nerve studies, brain imaging and genetic testing to try and differentiate the various subtypes of MND, develop markers of disease, and to identify the site of onset and the spread of disease. The goal of this clinical research will be to enable an early diagnosis, improve patient assessment and management, and provide new knowledge regarding nerve function in these patients. This overall insight will hopefully be able to advance the development of new treatment strategies.

MNDRA PhD Top-up Grant (2016 - 2018)
Lead Investigator: Emily McCann
Institution: Macquarie University 
Title: Investigating the genetic and epigenetic basis of amyotrophic lateral sclerosis
There is currently no cure or effective treatment for MND, and genetic mutations are the only proven cause. Approximately 10% of MND is hereditary, and only two thirds of these cases are accounted for by known genetic mutations, leaving the cause of most MND unsolved. We aim to uncover further genetic variants and patterns of DNA chemical modifiers (epigenetic markers) that underlie MND by interrogating samples from MND patients and their families. Identifying such signatures of MND will provide greater insight into the molecular physiological processes underlying disease. As such, our research has great potential to identify targets for future MND therapeutics, particularly epigenetic markers that are reversible and targeted by many currently available drugs.

Susie Harris Travel Fellowship 2016 
Lead Investigator: Dr Rebekah Ahmed
Institution: University of Sydney
Title: Eating behaviour and cognition in the ALS-FTD spectrum: effect on survival
This grant will allow Rebekah to work with collaborators at the Institute of Metabolic Sciences, Cambridge, UK, and to present the findings of her work at the International ALS/MND Symposium in Dublin, Ireland, in December 2016.

Jenny and Graham Lang Collaboration Travel Grant 2016
Lead Investigator: Dr Frederik Steyn
Institution: University of Queensland
Title: Re-evaluation of hypermetabolism and the assessment of endogenous adipose as a modifier of ALS/MND progression
This grant will assist visits to the laboratories of Professor Leonard van den Berg in the Netherlands and Professor Pierre-Francois Pradat in France. The award will strengthen and expand research to help define patients most likely to benefit from metabolic-directed therapies.