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MND research grants

MND researchers funded by MNDRIA 2017 MND Research Australia has awarded almost $4 million to support the best MND research commencing in 2019.

MNDRA is indebted to the generosity of donors, bequestors and the State MND Associations who fund this research.

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.

Two additional grants were awarded earlier in the year to support the NHMRC Partnership Grant and the Australian MND Registry.

PROJECTS COMMENCING IN 2019

BETTY LAIDLAW MND RESEARCH PRIZE 2019
Dr Marco Morsch Macquarie University, NSW	Betty Laidlaw MND Research Prize awarded to an outstanding mid-career researcher	Targeting the nucleo-cytoplasmic transport machinery in sporadic and familial ALS

POSTDOCTORAL FELLOWSHIPS (2019 – 2021)
Dr Rosemary Clark University of Tasmania, TAS	Bill Gole MND Postdoctoral Fellowship 2019 – 2021	Clinical heterogeneity in ALS: insights from interneurons?
Dr James Hilton University of Melbourne, VIC	Beryl Bayley MND Postdoctoral Fellowship 2019 – 2021	Ferroxidase dysfunction drives glial ferroptotic stress and motor neurone death via neurotoxic A1 astrocyte conversion

INNOVATOR GRANTS
Professor Julian Gold The Albion Centre, Prince of Wales Hospital, NSW Health	Charcot Grant awarded to the highest ranking innovator grant application	Phase 3 placebo controlled group sequential trial of Triumeq in patients with Motor Neurone Disease
Dr Rebekah Ahmed University of Sydney, NSW	Neil and Norma Hill Foundation MND Research Grant	Physiological changes along the frontotemporal dementia amyotrophic lateral sclerosis spectrum – The hypothalamus where eating, metabolism and neurophysiology meet
Professor Samar Aoun La Trobe University, VIC	MS WA MND Research Grant	Best practice in end-of-life care and bereavement support: A national survey of bereaved family carers of people with MND
Dr Catherine Blizzard University of Tasmania, TAS	Gross Foundation MND Research Grant	Can estrogen protect against synaptic disturbances in ALS?
Professor Roger Chung Macquarie University, NSW	MNDRA Innovator Grant	Revealing the role of protein clearance pathways in sporadic ALS
Dr Anthony Cook University of Tasmania, TAS	Janette Hamilton MND Research Grant	Proteomic analysis of exosomes from iPS cell-derived neurons with mislocalised TDP-43
Associate Professor Peter Crouch University of Melbourne, VIC	Jenny Barr Smith MND Research Grant	The neurotoxic consequences of glial iron accumulation in MND
Associate Professor Kay Double University of Sydney, NSW	Lady (Mary) Fairfax MND Research Grant	Validating molecular pathways of SOD1 toxicity in human ALS
Dr Michelle Farrar University of New South Wales, NSW	MNDRA Innovator Grant	Assessing preference heterogeneity with respect to MND treatment. A discrete choice experiment
Dr Jennifer Fifita Macquarie University, NSW	Peter Stearne Familial MND Research Grant	Investigating the role of large structural variation in MND by analysis of whole-genome sequencing data
Associate Professor Nimeshan Geevasinga Western Sydney Local Health District, NSW	Jenny Simko MND Research Grant	Utilising novel MRI connectomic analysis to explore pathophysiological changes in ALS
Dr John Lee University of Queensland, QLD	Col Bambrick MND Research Grant	Investigating the beneficial effects of complement C3aR on immune cell glucose metabolism in MND
Associate Professor Seth Masters The Walter and Eliza Hall Institute of Medical Research, VIC	Superball XI MND Research Grant	Targeting cGAS/Sting to block neuroinflammation in MND
Professor Pamela McCombe University of Queensland, QLD	Jenny Simko MND Research Grant	Immunogenetics of motor neurone disease - a pilot study
Dr Fiona McKay University of Sydney, NSW	MonSTaR MND Research Grant	Anti-inflammatory and metabolic effects of dimethyl fumarate in amyotrophic lateral sclerosis
Dr Parvathi Menon Western Sydney Local Health District, NSW	MNDRA Innovator Grant	ALS progression: multimodal approach to assessing cortical dysfunction which may underlie pathogenesis
Dr Sean Millard University of Queensland, QLD	Fat Rabbit MND Research Grant	Identifying molecular pathways affected by the sporadic ALS risk factor, GGNBP2
Dr Sarah Rea The University of Western Australia, WA	MS WA MND Research Grant	Defining the interaction between p62 and TDP-43 as a potential therapeutic target for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Dr Mary-Louise Rogers Flinders University of South Australia, SA	Andrew Butcher MND Research Grant	How does Triumeq work as an MND treatment? A study to determine the relationship between endogenous retrovirus, TDP43 pathology and inflammatory signals in MND
Dr Rachel Tan University of Sydney, NSW	Benalla Act to d'feet MND Research Grant	Prions, RNA binding proteins with prion-like domains and motor neuron degeneration
Professor Julian Trollor University of New South Wales, NSW	Mavis Gallienne and Graham Lang MND Victoria Research Grant	Using big data to understand the health status and service use of people with motor neurone disease
Dr Mehdi van den Bos Western Sydney Local Health District, NSW	MNDRA Innovator Grant	Cortigofugal dysfunction and cortical hyperexcitability in ALS – a window into ALS onset and progression utilising TMS EEG
Professor Mark Wilson University of Wollongong, NSW	MonSTaR MND Research Grant	Rapid screening of small molecule libraries to identify new drug leads to treat Motor Neurone Disease
Associate Professor Trent Woodruff University of Queensland, QLD	NTI MND Research Grant	Manipulation of free fatty acid receptors to tame the immune response in MND
Associate Professor Justin Yerbury University of Wollongong, NSW	Dr Paul Brock MND NSW Research Grant	Is UBA1 a therapeutic target in ALS?

MNDRA PhD SCHOLARSHIP TOP-UP GRANTS 2019 - 2021
Megan Dubowsky Flinders University, SA	MNDRA PhD Scholarship Top-Up Grant 2019 - 2021	Endogenous retroviruses as a cause of motor neurone disease
Marcus Dyer University of Tasmania, TAS	MNDRA PhD Scholarship Top-Up Grant 2019 - 2021	Neuronal excitability in ALS – a focus on TDP-43 mislocalisation

OTHER GRANTS COMMENCING IN 2019
Professor Matthew Kiernan Brain and Mind Centre, University of Sydney	NHMRC Partnership Grant	MND: Patient-centred care for a progressive neurological disease - evidence driving policy
Associate Professor Paul Talman Barwon Health, VIC	Lord Mayor's Charitable Foundation - Eldon & Anne Foote Trust	Australian Motor Neurone Disease Registry

MULTI-YEAR GRANTS FROM PREVIOUS YEARS CONTINUING IN 2019

MND AUSTRALIA ICE BUCKET CHALLENGE GRANT (2016 – 2019)
Professor Naomi Wray University of Queensland	MND Australia Ice Bucket Challenge Grant 2016 – 2019	Sporadic ALS Australian Systems Genomics Consortium (SALSA-SGC)

POSTDOCTORAL FELLOWSHIPS (2018 – 2020)
Dr Nirma Perera Florey Institute of Neuroscience and Mental Health, VIC	Bill Gole MND Postdoctoral Fellowship 2018 – 2020	Targeting autophagy protein homeostasis pathway to improve motor neurone health in MND
Dr William Huynh Brain and Mind Centre, University of Sydney, NSW	Beryl Bayley MND Postdoctoral Fellowship 2018 – 2020	A multimodal approach combining novel electrophysiological and neuroimaging techniques to explore the pathophysiological mechanisms and patterns of disease spread in MND

POSTDOCTORAL FELLOWSHIPS (2017 – 2019)
Dr Jennifer Fifita Macquarie University, NSW	Bill Gole MND Postdoctoral Fellowship 2017 – 2019	Investigating the molecular and pathological origins of amyotrophic lateral sclerosis
Dr Emma Devenney Brain and Mind Centre, University of Sydney, NSW	Beryl Bayley MND Postdoctoral Fellowship 2017 – 2019	Behaviour, cognition, eye-movements and psychiatric disease in C9orf72 MND and FTD; a cross modal-approach to facilitate early and accurate diagnosis

MNDRA PhD SCHOLARSHIP TOP-UP GRANTS
Camille Paynter University of Melbourne, VIC	MNDRA PhD Scholarship Top-Up Grant 2018 - 2020	A longitudinal study of involvement in health care decision-making in motor neurone disease: Patient and caregiver perceptions, impact of communication and swallowing difficulties, and quality of life
Britt Berning Queensland Brain Institute, QLD	MNDRA PhD Scholarship Top-Up Grant 2018 - 2020	Sub-cellular dysfunctions associated with pathological TDP-43 in MND: disease mechanisms and therapeutic relevance
Timothy Tracey The University of Queensland, QLD	MNDRIA PhD Scholarship Top-Up Grant 2017 - 2019	Using in vitro human cortical neurons as a model to study neurometabolic defects in motor neuron disease

NHMRC/MNDRA POSTGRADUATE SCHOLARSHIP (2017 – 2019)
Camille Paynter University of Melbourne	NHMRC/MNDRA Postgraduate Scholarship	Communication, quality of life and advance care planning for people with MND and their caregiver

FULL DESCRIPTIONS – PROJECTS COMMENCING 2019

Betty Laidlaw MND Research Prize

Dr Marco Morsch
Macquarie University, NSW

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)

Dr Rosemary Clark
University of Tasmania, TAS

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)

Dr James Hilton
University of Melbourne, VIC

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 copperiron 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

Professor Julian Gold

The Albion Centre, Prince of Wales Hospital, NSW Health

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 costeffective.

Neil and Norma Hill Foundation MND Research Grant

Dr Rebekah Ahmed
University of Sydney, NSW

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

Professor Samar Aoun
La Trobe University, VIC

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 endof-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 indepth 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

Dr Catherine Blizzard
University of Tasmania, TAS

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

Professor Roger Chung
Macquarie University, NSW

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

Dr Anthony Cook
University of Tasmania, TAS

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

Associate Professor Peter Crouch
University of Melbourne, VIC

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

Associate Professor Kay Double

University of Sydney, NSW

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

Dr Michelle Farrar
University of New South Wales, NSW

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

Dr Jennifer Fifita
Macquarie University, NSW

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

Associate Professor Nimeshan Geevasinga
Western Sydney Local Health District, NSW

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

Dr John Lee

University of Queensland, QLD

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

Associate Professor Seth Masters
The Walter and Eliza Hall Institute of Medical Research, VIC

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

Professor Pamela McCombe
University of Queensland, QLD

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

Dr Fiona McKay

University of Sydney, NSW

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

Dr Parvathi Menon
Western Sydney Local Health District, NSW

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

Dr Sean Millard
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

Dr Sarah Rea
The University of Western Australia, WA

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

Dr Mary-Louise Rogers
Flinders University of South Australia, SA

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 trialed 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

Dr Rachel Tan
University of Sydney, NSW

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

Professor Julian Trollor
University of New South Wales, NSW

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

Dr Mehdi van den Bos

Western Sydney Local Health District, NSW

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

Professor Mark Wilson
University of Wollongong, NSW

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

Associate Professor Trent Woodruff

University of Queensland, QLD

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

Associate Professor Justin Yerbury
University of Wollongong, NSW

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.

MNDRA PhD Scholarship Top-Up Grants (2019 – 2021)

Megan Dubowsky
Flinders University, SA

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.

Marcus Dyer
University of Tasmania, TAS

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.

NHMRC Partnership Grant

Professor Matthew Kiernan
Brain and Mind Centre, University of Sydney

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

Associate Professor Paul Talman

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 geonomics, 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.

ONGOING RESEARCH PROJECTS

SALSA-SGC GRANT (2016 – 2020)
Professor Naomi Wray
University of Queensland, QLD

Sporadic ALS Australian Systems Genomics Consortium (SALSA-SGC)

The outcome of our project will be identification of new risk genes for ALS and a nationwide strategy for genomic research through the new Sporadic ALS Australian Systems Genomics Consortium (SALSA-SGC). Identification of new risk genes will build a more complete picture of the underlying mechanisms and pathways for disease. Each new molecule offers a unique opportunity to dicover mechanisms leading to neurodegeneration. Any new ALS molecule is potentially a new therapeutic target.

Beryl Bayley MND Postdoctoral Fellowship (2018 – 2020)

Dr William Huynh
Brain and Mind Centre, University of Sydney

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)

Dr Nirma Perera

Florey Institute of Neuroscience and Mental Health, VIC

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.

Beryl Bayley MND Postdoctoral Fellowship (2017 – 2019)

Dr Emma Devenney
Brain and Mind Centre, University of Sydney, NSW

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)

Dr Jennifer Fifita
Macquarie University, NSW

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.

MNDRA PhD Scholarship Top-Up Grants (2018 – 2020)

Camille Paynter
University of Melbourne, VIC

A longitudinal study of involvement in health care decision-making in motor neurone disease: Patient and caregiver perceptions, impact of communication and swallowing difficulties, and quality of life.

Many people with MND will experience communication impairment. Difficulty with communication results in vulnerability, reduced quality of life and increased reliance on caregivers for communication support. By improving our understanding of the experiences of people with MND and their caregivers about their involvement in healthcare decision-making, we can enhance patient-centred practice.
This research will explore the facilitators and barriers for effective involvement in healthcare decision-making in MND particularly focusing on the impact of a communicating impairment. Interviews will be conducted over 12-18 months to uncover how decision-making changes over time, as disease progresses, and function and communication deteriorates.
The complexity of decision-making in MND will be captured through the longitudinal mixed methods design of this research.

Britt Berning
Queensland Brain Institute, QLD

Sub-cellular dysfunctions associated with pathological TDP-43 in MND: disease mechanisms and therapeutic relevance

Motor neurons are complex cells that require the precise and efficient movement of many different internal parts to survive. I aim to discover molecules that may be targeted for the development of new treatments for patients with MND by investigating how the movement of different parts of motor neurons is affected in disease. I will take a multi-faceted approach, combining a mouse model of MND with studies in cell culture and human brain and spinal cord samples. Manipulating key pathways related to subcellular movement may prevent neuron death and help remove the toxic aggregates that are a hallmark of MND.

MNDRA PhD Scholarship Top-Up Grant (2017 – 2019)

Timothy Tracey
The University of Queensland, QLD

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.

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