The
MND Research Committee approved MNDRIA grants to the following researchers to assist with their projects commencing in 2015.
For more information on a project, please click the name of the researcher or click
here.
New grants awarded by MNDRA to commence in 2015 |
MND Australia Ice Bucket Challenge Grant |
Professor Naomi Wray
Queensland Brain Institute, University of Queensland |
Sporadic ALS Australian Systems Genomics Consortium (SALSA-SGC) |
Postdoctoral Fellowships |
BMRI, University of Sydney
|
Hyperexcitability of the lower motor neuron in ALS |
Bill Gole Postdoctoral MND Research Fellowship |
Westmead Hospital,
University of Sydney
|
Insights into ALS pathophysiology from patterns of disease progression |
Beryl Bayley Postdoctoral MND Research Fellowship |
Grants-in-aid |
Grant recipient |
Project title |
Grant awarded |
ASAM, Macquarie University
|
Optimising the protective activity of protein disulphide isomerase in motor neuron disease |
Angie Cunningham Laugh to Cure MND Grant |
ASAM, Macquarie University
|
Next-Generation Sequencing of Australian sporadic MND patients to identify genetic risk factors |
MND Ice Bucket Challenge Grant-in-aid |
Menzies, University of Tasmania
|
Synaptic dysfunction: an early mechanism of TDP-43 pathogenesis in ALS |
MNDRIA Grant-in-aid |
ASAM, Macquarie University
|
Proteomic studies to identify the defects caused by mutations in a newly identified familial MND gene |
Mick Rodger Benalla MND Research Grant |
Menzies, University of Tasmania
|
Inhibitory regulation of motor neurons: A new target mechanism for ALS? |
Mick Rodger MND Research Grant |
University of Melbourne
|
Determining the mechanism of toxicity of C9ORF72 RAN translation products |
Peter Stearne Familial MND Research Grant |
UQ Centre for Clinical Research
|
Blood biomarkers in ALS: Translation into clinical practice of pNfH and search for additional biomarkers using proteomics |
Graham Lang Memorial MND Research Grant |
Macquarie University
|
Decision support tools for motor neurone disease multidisciplinary care. |
MND Victoria Research Grant |
Dept of Anatomy, University of NSW
|
Novel MND mouse models |
MNDRIA Grant-in-aid |
UQ Centre for Clinical Research
|
A multicentre study of the impact of metabolic balance and dietary intake on the clinical parameters of disease progression |
Cunningham Collaboration Grant |
Garvan Institute of Medical Research
|
Genomic approach to find new MND disease genes and drug targets |
Terry Quinn MND Research Grant |
UQ School of Biomedical Sciences
|
In search of novel MND therapeutics: investigating the role of selective KATP channel activators on cortical hyperexcitability, corticospinal circuit degeneration, and cortical bioenergetics |
Bob Delaney MND Research Grant |
UQ School of Biomedical Sciences
|
The role of altered neuromuscular activity and mRNA transport in modifying the progression of MND |
MNDRIA Grant-in-aid |
Neuroscience Research Australia
|
Histopathological changes in functional zones of the cerebellum across the MND-FTD continuum |
MNDRIA Grant-in-aid |
Florey Institute of Neuroscience & Mental Health
|
Androgen receptor abnormalities in MND |
Ted Dimmick Memorial MND Research Grant |
Westmead Millenium Institute,
University of Sydney
|
Safety and biological efficacy of narrow-band UVB phototherapy in ALS |
MNDRIA Grant-in-aid |
ASAM, Macquarie University
|
Epigenomic approaches to understand MND disease variability |
Rosalind Nicholson MND Research Grant |
UQ School of Biomedical Sciences
|
Therapeutic targeting of the NLRP3 inflammasome using a potent and orally active inhibitor in experimental MND |
Charles & Shirley Graham MND Research Grant |
IHMRI, University of Wollongong
|
Monitoring accumulation of ubiquitin chains in ALS – Developing a potential imaging tool for monitoring preclinical disease progression |
Zo-ee MND Research Grant |
NHMRC/MNDRIA Co-funded Postgraduate Scholarship |
Nicole Sheers
Institute of Breathing and Sleep, Austin Health |
Lung Volume Recruitment in Neuromuscular Disease: Can "breathing-stacking" improve lung function, respiratory symptoms and quality of life in people with neuromuscular disorders? |
NHMRC/MNDRIA Co-funded Postgraduate Scholarship |
MNDRIA PhD Scholarship Top-up Grant |
Victoria McLeod
Florey Institute of Neuroscience & Mental Health |
Androgen Receptor Dysregulation in ALS |
MNDRIA PhD Scholarship Top-up Grant |
Travel Scholarships |
Dr Nimeshan Geevasinga
University of Sydney |
Novel diagnostic algorithm for ALS
Cortical excitability insights into Riluzole and ALS |
Susie Harris Travel Fellowship |
Dr Emily Don
Australian School of Advanced Medicine, Macquarie University |
Generation of individualised zebrafish models of MND |
Jenny & Graham Lang Collaboration Travel Grant |
Project Summaries for MNDRA-funded projects 2015
MND Australia Ice Bucket Challenge Grant 2015 – 2017
Professor Naomi Wray
Queensland Brain Institute, University of Queensland
> Sporadic ALS Australian Systems Genomics Consortium (SALSA-SGC)
The biological basis of MND (also known as ALS) is complex and poorly understood. Nevertheless, there have been dramatic advances in MND research in the past five years that have been driven, almost entirely, by gene discoveries from families with more than one affected individual (familial MND). These have opened new chapters in MND research. Recent advances in technology mean that sporadic cases (90% of all cases of MND) can also contribute to gene discovery, but DNA from those affected is needed. We estimate that less than half of those with MND in Australia are currently recruited into genetic studies.
Here, we propose to build an integrated infrastructure for collection of biological samples and clinical data. Our proposal brings together clinicians from the major MND clinics across Australia. This new initiative will generate a research resource that will underpin future research and position future MND patients to benefit from advances made through genomic medicine.
In this proposal we will build upon the growing MND/ALS genomics resource and contribute to the international genomics initiatives. The sixteen investigators of our proposal bring expertise in MND genetics and genomic analysis integrated with clinical interpretation. The interpretation of analyses of genetics data will be assisted by three international associate investigators. The outcome of our project will be identification of new risk genes for MND and a nationwide strategy for genomic research through the new Sporadic ALS Australian Systems Genomics Consortium.
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 discover mechanisms leading to neurodegeneration. Any new MND molecule is potentially a new therapeutic target.
Bill Gole MND Postdoctoral MND Research Fellowship 2015 – 2017
Dr James Howells
BMRI, University of Sydney, NSW
> Investigating the role of oligodendrocytes in ALS
Involuntary twitching of muscles (fasciculations) are characteristic of MND. Fasciculations are spontaneous ectopic motor unit discharges that arise predominantly in the distal parts of the peripheral nervous system. Recent evidence indicates that they are the earliest detectable abnormality in ALS, preceding by several months evidence of degeneration. Despite their importance it is not clear how fasciculations are generated or how they are related to motor neuron degeneration.
This research program will focus on the membrane properties of lower motor neurons in ALS, and in particular changes responsible for altered excitability and ectopic activity. We hypothesize that:
1. The characteristic fasciculations of MND are driven by early pathological alterations in the ‘excitability machinery’ of peripheral motor axons and that these changes can be profiled using noninvasive excitability testing techniques.
2. That the diminution of fasciculation in patients with advanced MND is due to the preferential degeneration of the larger and faster axons and thereby may be a marker of those motoneurons at greatest risk.
We aim to characterize the excitability and variability of lower motor neurons in MND and in doing so improve the accuracy of the motor unit scan (an essential indicator of disease progression).
Beryl Bayley Postdoctoral MND Research Fellowship 2015 – 2017
Dr Parvathi Menon
Westmead Hospital, University of Sydney, NSW
> Insights into ALS Pathophysiology from patterns of disease progression
The aim of my project is to better understand patterns of spread of Motor Neuron Disease and the mechanisms underlying it specifically a phenomenon called cortical hyperexcitability which in previous studies has been shown to be an early disease feature and to precede the onset of clinical disease in people with a genetic predisposition.
Disease spread has been studied earlier though mostly by patient examination and usually by retrospective analysis. The unique feature of my project will be prospective follow up of patients and supplementation of clinical examination by sensitive testing techniques for brain and nerve function. Disease onset in a body region is well known to precede obvious weakness raising the need for special functional diagnostic tests to supplement our examination techniques.
Understanding the mechanisms underlying disease onset and progress would help identify better treatment targets. Identifying cortical hyperexcitability as an early diagnostic marker of MND would reduce the current diagnostic delay and enable earlier introduction of treatment measures including recruitment of eligible patients into available treatment trials.
Overall, the aim of my project is to improve understanding of the disease processes underlying MND thereby working towards better treatment options in the near future and cure in the longer term.
Angie Cunningham Laugh to Cure MND Grant
A/Prof Julie Atkin
ASAM, Macquarie University, NSW
> Optimising the protective activity of protein disulphide isomerase in motor neuron disease
ALS/MND is a devastating disease and currently there is no effective therapeutic treatment, hence there is a great unmet need to identify new treatments that address the underlying pathology. One pathology common to the diverse forms of ALS/MND is the formation of abnormal protein clumps or ‘inclusions’ in affected motor neurons. We have identified a type of protein called a ‘chaperone’ that prevents these abnormal clumps from forming, and is protective against multiple other pathological events that occur in motor neuron cells in ALS. Whilst this chaperone is protective, it cannot by itself be used as a new drug because it is a large molecule and cannot be efficiently delivered to the brain. Hence in this proposal we aim to identify which specific features of this protein are responsible for its protective ability, so that new, drug-like molecules can be designed, based on its protective features. Secondly we will also characterise the protective activity of this protein in new disease models based on zebrafish, so that in the future, screening for new drugs can be performed in these animals, based on this chaperone protein. This study therefore aims to develop novel treatments for ALS/MND.
MND Ice Bucket Challenge Grant-in-aid
A/Prof Ian Blair
ASAM, Macquarie University, NSW
> Next-Generation Sequencing of Australian sporadic MND patients to identify genetic risk factors
Around 90% of MND cases have no known cause. There is strong evidence that this sporadic MND is caused by the combination of genetic factors (genetic variations that confer risk to MND) and environmental exposure. Indeed, current evidence indicates that genetic factors and environmental factors contribute about equally to the development of sporadic MND. Our aim is to identify genetic factors that predispose to MND or change the pattern of disease, such as age-of-onset, disease spread and duration. In general, common gene variations only contribute a small amount to the risk of disease, while rare variations contribute a lot. The identity of these genetic variations can help us understand the mechanisms underlying MND and therefore lead ultimately to rational therapies.
Dramatic advances in technology mean that we can now search for rare gene variations using a technique called Next-Generation Sequencing. This method determines the entire genome sequence of each patient. The result is a huge list of gene variations that can only be understood in the context of thousands of similar sequences from those with, and without, MND. We are therefore collaborating with other large international initiatives in which large-scale Next-Generation Sequencing data will be collected from thousands of individuals, and shared across countries and research groups to identify the genetic factors that confer risk to developing MND. This international collaboration will be the largest genetic study ever proposed for MND.
MNDRA Grant-in-aid
Dr Catherine Blizzard
Menzies, University of Tasmania, Tasmania
> Synaptic dysfunction: an early mechanism of TDP-43 pathogenesis in ALS
Amyotrophic Lateral Sclerosis (ALS) is a devastating disease that is caused by the death of motor neurons. There is a desperate need to discover new therapeutic ways to stop this neuron death, ideally targeted at early changes in the disease to prevent the majority of cell loss. Synapses are specialised structures that allow neurons to communicate with each other. Disturbances in neuronal synapses may be one such early event that potentially leads to neuronal dysfunction and then death. Changes in synapses can have serious effects on neurons’ activity levels and if not controlled can cause neuron death.
Mutations in the DNA editing protein TDP-43 causes a genetic form of ALS. TDP-43 has recently been shown to be involved in maintaining synapses between neurons; regulating the number and maturation of spines. It is feasible that an early disease-causing event in ALS may be changes to synapses. We will investigate how different mutations of the TDP-43 protein determines the number and composition of synapses in vitro using specialised compartmentalised primary neuronal cultures. This novel research program addresses an important gap in the current understanding of how synaptic changes can lead to neuron death in ALS and may open up a new target for drug intervention in this devastating disease.
Mick Rodger Benalla MND Research Grant
Prof Roger Chung
ASAM, Macquarie University, NSW
> Proteomic studies to identify the defects in protein-protein interactions and cellular signalling pathways caused by mutations in a newly identified familial MND gene
Our team has recently identified new mutations in a gene responsible for ALS in an Australian family, and through international collaborations has identified mutations in this gene in Canadian, US and European ALS patients. This represents a new major discovery in ALS genetics. This ALS gene encodes a protein that is directly involved in protein degradation and recycling in motor neurons, and our preliminary studies indicate that ALS mutations in this gene lead to abnormal accumulation of proteins within the cell, leading to neurodegeneration. This project will use a series of experimental techniques to precisely identify the specific proteins and signaling pathways that are impaired in motor neurons expressing mutations in this new ALS gene. Because abnormal protein degradation and the inappropriate accumulation of proteins inside motor neurons is observed in all forms of ALS/MND, the outcomes of this project will lead to greater understanding of the molecular causes of the disease.
Mick Rodger MND Research Grant
A/Prof Tracey Dickson
Menzies Research Institute, University of Tasmania, Tasmania
> Inhibitory regulation of motor neurons: A new target mechanism for ALS?
There is considerable evidence from many areas of clinical and basic medical research that in MND motor neurons may be dying due to a toxicity that is triggered due to their over activity – known as excitotoxicity. We and others have new evidence that this toxic cascade 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. We have developed a method of specifically growing interneurons and/or motor neurons, derived from transgenic mice developed to model MND, in primary culture. This highly specific ‘brain in a dish’ approach will allow us to determine if the presence of abnormal or pathogenic interneurons can lead to abnormal motor neuron function and pathology. Not only would these studies provide important insight into the mechanisms responsible for ALS, but they would also provide a high throughput model for later assessing potential therapeutic interventions.
Peter Stearne Familial MND Research Grant
Dr Danny Hatters
University of Melbourne, Victoria
> Determining the mechanism of toxicity of C9ORF72 RAN translation products
In 2011, mutations in the C9ORF72 gene were discovered to be the commonest cause of inherited forms of MND accounting for 40% of all inherited cases. In addition, the mutations are found in 7% of the sporadic cases as well as familial and sporadic forms of the closely related disease Frontotemporal Dementia. Recent discoveries have suggested that the mutations cause the gene to turn on the production of junk proteins that are not normally ever meant to be produced. These junk proteins accumulate in the brain of MND patients and have been postulated to be toxic to the neurons. Our research is aimed at determining how these junk proteins interfere with the normal functioning of cells and the extent to which they might be toxic. This knowledge is expected to inform the development of therapeutic strategies targeting the mutant C9ORF72 gene.
Graham Lang Memorial MND Research Grant
Dr Robert Henderson
UQ Centre for Clinical Research, Queensland
> Blood biomarkers in ALS: Translation into clinical practice of pNfH and search for additional biomarkers using proteomics
In MND, a biomarker that can predict disease severity and measure disease progression is needed for assessment of individual patients and also for clinical trials. There is no existing marker and using survival as a marker is flawed. A marker needs to be practical, applicable to all stages of disease and able to be applied equally in different MND centres. In this study we will expand on our preliminary work that appears to show that pNfH measured in the blood has potential to be a useful marker. We need to prove this in a prospective study, by comparing with other markers and in a larger number of subjects. A second part of the study will be to look for other biomarkers using mass spectrometry of plasma from subjects with MND. One important by-product of this project is that the blood samples are available for other MND research at 3 different centres in Qld and NSW.
MND Victoria Research Grant
Dr Anne Hogden
Macquarie University, NSW
> Decision support tools for motor neurone disease multidisciplinary care
People with MND and their families face many decisions for symptom management and quality of life. Patients and their family members value information about MND from sources they trust, such as MND associations, MND clinics and research-based websites. However, many people report feeling overwhelmed by the amount of information needed to manage their condition, and the confronting nature of that information. We know that difficulties coping with the impact of MND can cause patients to delay healthcare decisions, putting their safety and quality of life at risk. An effective way to present patients with specific, research-based information is through the use of decision support tools. Decision support tools have been used in chronic disease and cancer care to help patients make healthcare decisions as their condition deteriorates. The tools summarise the best practice options for symptom management, and inform patients of the risks and benefits associated with these options. Patients are then able to make informed decisions, and discuss the available options with family and health professionals. Currently, there are no decision tools designed to guide MND patients through treatment decisions.
This project aims to develop MND-specific tools to support major treatment decisions, including: use of riluzole; assisted ventilation; artificial feeding and hydration; end of life care; and saliva management. Additional tools, including equipment use and advance care planning, will be developed as the study progresses. The study team will produce paper and electronic tools, and investigate the development of phone app formats.
MNDRIA Grant-in-aid
Prof Lars Ittner
Dept of Anatomy, University of NSW, NSW
> Novel MND mouse models
The aim of the proposed study is to understand the role of profilin 1, a factor interacting and regulating the cytoskeleton in cells, in development and progression of MND. Mutations in the profilin 1 gene have recently been identified in three independent families with MND history. Experiments in cultured cells showed that the disease-causing mutations in profilin 1 compromise its ability to maintain cytoskeleton integrity and thereby contributing to functional impairments. However, these studies are limited to cell cultures, since there is no animal model to perform in vivo experiments. This application will close this gap and develop a series of novel MND mouse models based on profilin 1. Experiments in these mice will be complemented by live cell culture studies. Professor Ittner has extensive experience with the generation of genetic mouse models of neurodegenerative diseases. It is anticipated that this project will significantly enhance the understanding of principle mechanisms that lead to MND and further will provide novel mouse models for the development and testing of new therapies.
Cunningham Collaboration Grant
Prof Pamela McCombe
UQ Centre for Clinical Research, Queensland
> A multicentre study of the impact of metabolic balance and dietary intake on the clinical parameters of disease progression
People with MND show a loss of fat mass throughout the course of disease. This change in fat mass in MND is of clinical importance as a rapid loss of fat mass is associated with worse disease outcome. The underlying cause for the loss of fat mass appears to be linked to an increase in metabolism, which drives an increase in energy demand from the body. Interestingly, it has been reported that MND patients who receive high protein, high carbohydrate, or high fat supplements in their diet are able to maintain or increase their body weight. This in turn has been associated with improved outcome. Whether the benefits associated with dietary supplements in MND patients is due to an improved ability to meet energy demands because of the availability of excess calories remains unknown. Thus, this project aims to conduct a multicentre study that will assess relationship between metabolic balance and dietary intake, and the impact of this relationship on disease progression in MND patients. By identifying ways in which we can help the body to sustain optimal energy needs, we hope to develop metabolic strategies that have the potential to improve prognosis in MND.
This project will also develop collaboration between the RBWH/UQ MND group and the Netherlands MND centre in Utrecht.
Terry Quinn MND Research Grant
Dr Greg Neely
Garvan Institute of Medical Research, NSW
> Genomic approach to find new MND disease genes and drug targets
There are about 350,000 MND patients in the world. Currently, there are no effective therapies. Therefore, identifying potential drug targets for treatment of MND will help us address a large unmet medical need. MND involves a strong genetic component, although much of the genetics of MND remain to be identified. Recent genome-wide association studies (GWAS) have revolutionized our search for MND susceptibility loci, but these results are correlative and require functional validation to pinpoint bona fide MND disease genes and new drug targets.
In this proposal, human association efforts will be combined with functional target validation in Drosophila melanogaster (Fruit Fly) to evaluate all candidate human MND genes (~430 candidate MND disease genes). Specifically, the expression of each gene will be knocked-down in neurons and MND-like phenotypes such as basic motor coordination and lifespan will be evaluated in vivo. Since defects in synaptic development and function have been linked to MND, candidate genes will be further examined for their synaptic function and ultrastructure using a broad set of synaptic assays that combine electrophysiology, high-resolution imaging and electro-microscopy. Additionally, we will identify genes that are capable of stopping MND disease when targeted in humanized fly models of MND.
On completion of this project, we will have identified and functionally validated genes that can either cause or stop MND disease progression. Our results may lead to new strategies for early diagnosis and treatment of MND.
This project will also develop collaboration between the RBWH/UQ MND group and the Netherlands MND centre in Utrecht.
Bob Delaney MND Research Grant
Dr Shyuan Ngo
UQ School of Biomedical Sciences, Queensland
> In search of novel MND therapeutics: investigating the role of selective KATP channel activators on cortical hyperexcitability, corticospinal circuit degeneration, and cortical bioenergetics
In people with MND, brain cells that are involved in controlling movement have increased activity. While the only drug that is available for the treatment of MND (riluzole) works by controlling cell activity, it only provides a modest improvement in survival. Because increased cell activity is believed to be one of the primary factors that lead to the death of these brain cells and their connections, the identification of compounds with improved efficacy over riluzole is critical as this may greatly improve the effectiveness of current treatment strategies.
We will investigate a class of proteins that control cell activity by responding to the energy levels inside the cell. Substantial evidence suggests that in MND, changes in how the body uses energy contributes to the progression of disease. We therefore believe that the brain cells involved in controlling movement are unable to produce enough energy to sustain their survival. We also believe that the energy sensitive proteins on these cells do not respond to the energy deficit in the right way. Because of this, they are unable to assist in controlling cell activity, and this would contribute to the death of the cell. Using a mouse model of MND, we will test the effect of a novel compound that has been found to act on these energy sensitive proteins. We believe that by helping these proteins to function in the right way, this compound will normalise cell activity, and prevent the loss of these brain cells and their connections.
MNDRA Grant-in-aid
A/Prof Peter Noakes
UQ School of Biomedical Sciences, Queensland
> The role of altered neuromuscular activity and mRNA transport in modifying the progression of MND
There is evidence that abnormalities in the connections between motor nerves and muscle occur early in MND. Recent research has revealed three alterations in communication between motor neurons and muscle that are likely early modifying factors in MND. They include: i) alterations in the transport of important mRNAs from the motor neuron’s cell body within the spinal cord, to the motor nerve ending within muscle. These mRNAs make specific proteins needed for motor neurons to effectively contract muscle; ii) a decline in the signalling between motor nerves and muscle that stabilizes their connections; and iii) abnormally increased motor neuron activity. To investigate how these alterations trigger MND, we propose to re-construct the human neuromuscular circuit in culture from cells derived from MND and control patients. Skin cells from MND and control patients will be differentiated into muscle and motor neurons and subsequently co-cultured to form motor neuron-muscle connections. By assessing the movement of mRNAs and their RNA binding proteins within the motor neuron and its nerve terminal ending, measuring the stability of neuromuscular connections over time, and artificially altering the activity of motor neurons in this culture system, we will be able to gain unprecedented insight into the causes of MND. In the process, we will also establish a novel drug-screening platform for MND, which could have therapeutic benefits for improving the muscle function in MND.
MNDRA Grant-in-aid
Dr Rachel Tan
Neuroscience Research Australia, NSW
> Histopathological changes in functional zones of the cerebellum across the MND-FTD continuum
The human cerebellum comprises 10% of total brain volume and is home to more neurons than any other brain region. The sheer enormity of this structure suggests a pivotal role in intact neurological function yet little is known about the cerebellum in MND. Recent findings in healthy humans demonstrate crucial cerebellar involvement in motor, cognitive and neuropsychiatric processes. Given that approximately 14% of patients with MND demonstrate cognitive and neuropsychiatric symptoms characteristic of behavioral variant frontotemporal dementia (bvFTD), these findings have cumulated to position the cerebellum at the centre of the MND-FTD continuum. We recently examined structural changes in cerebellar subregions across the MND-FTD continuum and demonstrated consistent cerebellar involvement, which impacts on motor, cognitive and neuropsychiatric processes. Histopathological analyses are required to determine the underlying changes that subserve regional cerebellar atrophy identified with these neuroimaging methodologies.
The goal of the proposed research is to identify specific neuronal populations targeted and characterise the pattern of protein accumulation in cerebellar subregions associated with the various MND-FTD syndromes. The outcomes of this study will provide crucial knowledge that will progress research into targeted disease-modifying agents for the treatment of MND and bvFTD syndromes.
Ted Dimmick Memorial MND Research Grant
Dr Bradley Turner
Florey Institute of Neuroscience & Mental Health, Victoria
> Androgen receptor abnormalities in MND
Androgens such as testosterone are important factors for proper development and survival of motor neurons. Androgens act on the androgen receptor (AR) to carry out their function. There is increasing evidence that androgens may play a role in MND, including the higher incidence of MND in males, abundance of AR in motor neurons and AR defects link to another motor neuron disorder, Kennedy's disease. We have new evidence that AR protein levels are lower in spinal cords of MND mice. Furthermore, AR loss occurs specifically in motor neurons in MND mice. We now wish to determine how early AR abnormalities occur in Petri dish and mouse models of MND. We will also establish the primary mechanism responsible for AR loss in MND. This may provide important insights into the potential contribution of AR to MND and whether AR presents a new disease player and potential therapeutic target for MND.
MNDRIA Grant-in-aid
A/Prof Steve Vucic
Westmead Millenium Institute, University of Sydney, NSW
> Safety and biological efficacy of narrow-band UVB phototherapy in ALS
ALS is unknown, recent evidence points to an important role for immune dysregulation in ALS pathogenesis. In particular, a role for the suppressive arm of the immune system, directed primarily by regulatory T cells (Tregs), may slow disease progression. In this project we will conduct the first trial in ALS of a specific immune therapy, narrow band UVB phototherapy, known to increase Treg activity.
For this, a team has been assembled with all relevant expertise. It is led by a clinician scientist with a long track record in ALS research and clinical care. Narrow band UVB phototherapy is a simple, safe and non-invasive treatment used routinely to suppress damaging immune reactions in other conditions such as psoriasis. We will determine whether UVB phototherapy is safe in ALS and whether it induces regulatory T cells. If effective, this would support a larger trial examining whether UVB phototherapy can slow the progression of disease.
Slowing disease progression using phototherapy would be a major advance for a devastating disease. If phototherapy has no effect on disease progression but can increase regulatory T cells it may be useful in combination with other neuron-regenerating treatments that are in development, by reducing immune-mediated neuron damage. The study proposed here will expand our knowledge of the role of the immune system in ALS and highlight the potential to harness its regulatory arm to slow disease progress.
Rosalind Nicholson MND Research Grant
Dr Kelly Williams
ASAM, Macquarie University, NSW
> Epigenomic approaches to understand MND disease variability
The only known causes of ALS are gene mutations, which account for only a small proportion of ALS cases. Patients with ALS experience very different diseases courses, with variable age of onset, clinical progression and duration of disease. Most interestingly, patients who possess identical genetic mutations can exhibit vast differences in these clinical features. This demonstrates that modifiers of disease other than genetic predisposition are at play. We have a unique opportunity to examine DNA samples from a large, well characterised Australian ALS patient cohort that present with different manifestations of the disease (e.g. early onset, rapidly progressing disease or long disease duration). We will search for physical changes to DNA that occur without altering the genetic code (epigenetic) that modify the onset and progression of ALS. Biostatistical analyses of these epigenetic changes aim to find specific epigenetic patterns that discriminate between the different subtypes of ALS and correlate with disease duration. If these disease modifiers can be identified, we will be well positioned to not only enhance our understanding of the biology of ALS, but to pinpoint potential therapeutic targets that may be able to enhance quality and duration of life for ALS patients.
Charles & Shirley Graham MND Research Grant
A/Prof Trent Woodruff
UQ School of Biomedical Sciences, Queensland
> Therapeutic targeting of the NLRP3 inflammasome using a potent and orally active inhibitor in experimental MND
Inflammation is a key process in the body’s natural defence against infection. However, when chronically activated in the absence of infection, it can also lead to progressive tissue damage. In the late 1990’s a new mechanism was identified which could regulate inflammatory damage in the brain. Our laboratory, and several other groups, have preliminary evidence that this inflammatory pathway is activated in MND. We hypothesise that over-activation of this pathway in MND brains leads to death of motor neurons, which accelerates disease progression. Our group has identified a novel, orally active drug, which can block this inflammatory pathway. In this study, our goal is to investigate the therapeutic potential of this drug in a preclinical mouse model of MND. We will also examine this pathway in the blood of MND patients, and also in brain samples of patients who have died of MND. This will provide vital proof-ofconcept data that therapeutic targeting of this inflammatory pathway may slow MND in humans. If our project is successful, it will pave the way for future clinical trials of drugs that target this inflammatory pathway in MND patients. Our group, consisting of experienced pharmacologists, medicinal chemists, neurologists, and immunologists, are well positioned to carry out this work.
zo-ee MND Research Grant
Dr Justin Yerbury
IHMRI, University of Wollongong, NSW
> Monitoring accumulation of ubiquitin chains in ALS – Developing a potential imaging tool for monitoring preclinical disease progression
Currently there are no effective treatments for MND. Although many drugs have showed promise in the laboratory none have translated to become symptom-slowing drugs in human trials. It has been proposed that MND may start inside motor neurons much earlier than previously thought, and potentially years before physical symptoms appear. We aim to develop an imaging molecule that would allow the detection of cellular dysfunction well before symptom onset. This project will build the foundations of an imaging molecule discovery pipeline allowing for the development of an imaging technique to detect the accumulation of specific targets in MND. It is possible that detecting the disease earlier may give the drugs that work in the lab setting more of a chance to work in people living with MND.
NHMRC/MNDRA Co-funded Postgraduate Scholarship
Nicole Sheers
Institute of Breathing and Sleep, Austin Health, VIC
> Lung Volume Recruitment in Neuromuscular Disease: Can ‘breath-stacking’ improve lung function, respiratory symptoms and quality of life for people with neuromuscular disease?
Not being able to take deep breaths and cough forcefully are two distressing consequences of the breathing problems that people with MND may face. In neuromuscular conditions such as MND, breathing complications are one of the main causes of discomfort, disability and ultimately death. Over time the lungs and rib cage become stiff, the lungs become smaller, how well you can breathe and cough reduces. Improving breathing function is therefore an important aim of treatment and may reduce symptoms, improve quality of life and survival.
Lung volume recruitment, also known as breath-stacking, is a simple and inexpensive therapy that may help. It involves performing a type of ‘deep breathing exercise’ using a special resuscitation bag for assistance. It is thought that breath-stacking might prevent chest stiffness, improve cough effectiveness, symptoms and quality of life but there is no strong evidence to prove these ideas.
This research trial will be the first in the world to properly investigate whether performing breath-stacking exercises daily for three months improves breathing function. We will look at the short and medium-term effects on the breathing system by measuring lung volumes, stiffness, symptoms, quality of life and cough effectiveness.
If breath-stacking is beneficial and lung volume, chest stiffness and cough effectiveness improve then symptoms, quality of life and potentially survival are likely to be better for people with MND. This research would provide evidence for more widespread use of breath-stacking and enhance the multi-disciplinary respiratory management of people living with MND and other neuromuscular disorders.
MNDRA PhD Scholarship Top-up Grant
Victoria McLeod
IHMRI, Florey Institute, VIC
> Androgen Receptor Dysregulation in ALS
Epidemiological studies of ALS indicate gender differences in incidence, age of onset and site of onset which is suggestive of hormonal involvement. Likewise there is evidence that androgens, such as testosterone, and anabolic steroids are linked to a negative prognosis in ALS. Androgens bind to the androgen receptor (AR) and carry out a wide variety of functions throughout the body. Most importantly androgen receptors can be found in high levels in several tissues affected by MND including motor neurons and skeletal muscle tissue. Further evidence for a potential role of AR in ALS comes from the similarities in the disease pathology with a motor neuron disorder, Kennedy’s disease, in which a mutation of the AR leads to loss of motor neurons in the spinal cord and brainstem.
This project aims to explore changes in AR expression and function in cellular and animal models of MND and how these changes potentially contribute to disease progression. This will be achieved by employing drug-based and genetic-based mechanisms to delete or amplify AR actions. We anticipate that the findings of this study will lead to a better understanding of the cellular mechanisms leading to disease pathology and identify new treatment targets.
Susie Harris Travel Fellowship 2015
Dr Nimeshan Geevasinga
University of Sydney, NSW
> Novel diagnostic algorithm for ALS & Cortical excitability insights into Riluzole and ALS
We hope to collaborate with the Ozdinler laboratory in Chicago and work with animal models of ALS. The Ozdinler lab have made great progress in looking at upper motor neurons in ALS, which are commonly affected in ALS and are thought to be where the disease process may begin. We have looked at this in patients by studying them with transcranial magnetic stimulation. However we have not looked at animal models to date. This collaboration will enable us to look at upper motor neurons in animal models and then compare these findings with what we find by studying human subjects with ALS. If we can help identify where the disease process may start, then we can target treatment approaches accordingly. I hope that by attending the Ozdinler laboratory we can learn, and formalize collaborations, where in the future we may share post mortem tissue between our clinical facility and the research facility at the Ozdinler laboratory.
Jenny & Graham Lang Collaboration Travel Grant 2015
Dr Emily Don
Australian School of Advanced Medicine, Macquarie University, NSW
> Generation of individualised zebrafish models of MND
An ongoing problem with MND research is the lack of animal models in which to explore the biological triggers that cause MND. This has sadly led to a lack of effective treatments for patients suffering from MND. With this grant, I will travel to the laboratory of Professor Ekker at the Mayo Clinic, USA where I learn world-leading gene editing techniques. I will be able to bring this knowledge back to Australia where I can use these groundbreaking gene editing techniques to generate zebrafish carrying a MND patient’s exact gene mutation. Through this collaboration I aim to create individualised zebrafish models of MND which we will use investigate the biological triggers of MND with the long-term goal that these individualized models will be used to screen for new, effective treatments for patients.
MNDRI-funded projects 2014
Bill Gole MND Postdoctoral Fellowship 2014 – 2016
Dr Jacqueline Leung
Wicking Dementia Research and Education Centre, University of Tasmania, Tasmania
> Investigating the role of oligodendrocytes in ALS
Amyotrophic Lateral Sclerosis (ALS) is characterised by the progressive loss of motor neurons in brain and spinal cord. The axons (longest processes of neurons) of the motor neurons are mostly wrapped by the oligodendrocytes that produce myelin, an insulating layer that allows rapid conduction of the neuronal signal. The oligodendrocytes have also recently been identified to play an important role in providing metabolic support to these axons. Recent evidence in ALS research has suggested that oligodendrocytes might have an active role in both disease onset and disease progression in ALS. This study will focus on understanding the role of oligodendrocytes in ALS and allow us to uncover specific mechanisms in the involvement of oligodendrocytes in ALS. The results collected from this study will contribute to a greater understanding of disease processes in ALS, as well as establishing new therapeutic targets in ALS treatments.
Jenny & Graham Lang Collaboration Travel Grant 2014
Dr Rebecca Sheean
Florey Institute of Neuroscience and Mental Health, Victoria
Travel to University of Oxford to work with Professor Kevin Talbot and the Oxford Motor Neuron Disease Group
> Development of survival motor neuron (SMN) gene therapy for MND
This project aims at investigating the therapeutics of delivery SMN in models of MND. There are a number of factors that implicate survival motor neuron (SMN) in MND including reduced copy number of SMN in MND patients.. We have shown loss of SMN in motor neurones expressing MND-linked genes (SOD1, TDP43) and in spinal cords of presymptomatic SOD1G93A mice suggesting that this is an early event in MND. In addition we have shown SMN depletion in spinal cords from sporadic MND patients, highlighting that loss of SMN occurs broadly in MND and is not restricted to familial forms of the disease. Therefore, we propose that SMN upregulation may be beneficial in MND. Preliminary data from our group has shown that increasing SMN expression is protective in models of MND. Transgenic mice neuronally overexpressing SMN protein (SMN Tg) were resistant to axotomy-induced motor neuron loss using a nerve injury model. Also, we have shown by crossing SMN Tg and mutant SOD1 mice that SMN upregulation delays disease onset and is protective against motor neuron loss. In this project we aim to investigate the therapeutic effects of SMN gene therapy using an immunogene approach in mouse models of MND.
Graham Lang Memorial MND Research Grant
Professor Samar Aoun
Curtin University, Western Australia
> Best practice in breaking the news of an MND diagnosis: A survey of patients, family carers and neurologists
Communicating a diagnosis of MND is challenging for clinicians and for patients. This project consists of an Australia wide survey on breaking the news of an MND diagnosis from the perspectives of patients, family carers and neurologists. The feedback from the 3 groups will assist in describing the experience of when and how the diagnosis was provided, in assessing the current practice of clinicians in breaking bad news, and in making recommendations for Australian MND specific guidelines.
MNDRA Grant-in-aid
Associate Professor Julie Atkin
Australian School of Advanced Medicine, Macquarie University, New South Wales
> Identifying novel pathological mechanisms linked to C9ORF72 in amyotrophic lateral sclerosis
Whilst many potential drugs have been trialled in ALS, to date, none have resulted in effective therapies. This reflects a lack of basic understanding of the underlying mechanisms that trigger disease. In the last two years, a mutation in a protein known as “C9ORF72” was identified as the major genetic cause of ALS, but the normal function of this protein and how the mutation causes the disease remains unknown. In this study we will investigate the disease mechanisms triggered by C9ORF72. Investigation of how this newly identified protein causes ALS is a critical step in understanding how disease develops, how motor neurons degenerate and eventually die. From these studies, effective therapeutics can be designed to treat ALS patients in the future.
MNDRA Grant-in-aid
Dr Mark Bellingham
School of Biomedical Sciences, University of Queensland, Queensland
> Respiratory motor dysfunction and treatment in an animal model of motor neuron disease
Despite the fact that death in MND is usually due to respiratory failure, and that respiratory function is one of the best predictive factors for disease progression, we know very little about how dysfunction develops in the neural control of breathing movements in MND. In particular, effective treatments for respiratory dysfunction are sadly lacking. The planned outcome of this research will be the first comprehensive characterization of the neural control of breathing movements and its progressive dysfunction in a commonly used mouse model of MND. This characterisation will range from the cellular to the systems level, from functional and structural changes in single respiratory motor neurons to breathing movements and responses to common breathing stimuli in the whole animal.
We will also test two novel therapeutic strategies – prophylactic early treatment with riluzole at a time when changes in motor neurons controlling breathing movements are already starting to occur, and the induction of enhanced breathing output (respiratory long-term facilitation) in both the early stages of disease, and in the dysfunctional adult breathing motor system. The outcomes of these treatment strategies will provide invaluable insights into how and when to treat breathing dysfunction in human MND.
Mick Rodger Benalla MND Research Grant
Dr Beben Benyamin
Queensland Brain Institute, University of Queensland, Queensland
> Trans-ethnic and trans-omic statistical analyses to identify new ALS risk variants
Elucidating the aetiology of ALS/MND is the key to its treatment and cure. Genetic factors are a major cause of ALS even in apparently sporadic cases (i.e. no family history of ALS). Currently, the known ALS genes explain a small proportion of sporadic cases. Except for age and sex, there are no specific biomarkers and environmental factors known affecting ALS. Using state-of-the-art genomic technologies, such as genome-wide association study, exome sequencing and epigenome-wide association study in ALS patients and controls, we aim to discover novel genes affecting ALS and to dissect their biological functions in ALS. To achieve these aims, we will use rich data from ~4,000 Chinese ALS case-control samples and summary GWAS data from the largest European ALS samples (ALSGEN Consortium). To our knowledge this will be the first large-scale trans-ethnic meta-analysis for ALS. We expect to identify novel genetic risk variants affecting ALS disease status or age of onset across ethnic populations and to understand their roles in ALS. An association between locus or genome-wide epigenetic states and ALS disease status or age of onset may lead to the discovery of novel pathways.
MNDRIA Grant-in-aid
Dr Catherine Blizzard
Menzies Research Institute Tasmania, Tasmania
> Synaptic alterations in ALS: A novel therapeutic target?
Amyotrophic Lateral Sclerosis (ALS) is a devastating disease that is caused by the death of motor neurons. There is a desperate need to discover new therapeutic ways to stop this neuron death, ideally targeted at early changes in the disease to prevent the majority of cell loss. Disturbances in neuronal synapses may be one such early event that potentially leads to neuronal dysfunction and then death. Synapses are specialised structures that allow neurons to communicate with each other. Changes in synapses can have serious effects on neurons’ activity levels and if not controlled can cause neuron death. In dendrites, the large structures that relay information to the neuron’s cell body, these synapses are present on small protrusions known as dendritic spines.
Mutations in the protein, transactive response DNA-binding protein 43 (TDP-43) causes a genetic form of ALS. TDP-43 has recently been shown to be involved in maintaining synapses between neurons; regulating the number and maturation of spines. It is feasible that an early disease-causing event in ALS may be changes to synapses. We will investigate how TDP-43 protein mutation determines the number and type of synapses on motor neurons in the brain and how these changes lead to dendritic spine alterations in ‘real time’ through a unique mouse model and sophisticated imaging techniques. This novel research program addresses an important gap in the current understanding of how synaptic changes can lead to neuron death in ALS and may open up a new target for drug intervention in this devastating disease.
Peter Stearne Grant for Familial MND Research
Dr Nicholas Cole
Australian School of Advanced Medicine, Macquarie University, New South Wales
> Modeling the ALS-linked C9ORF72 hexanucleotide repeat expansion in zebrafish
Despite many years of research on amyotrophic lateral sclerosis (ALS), there is little understanding of the basic biology that results in a person acquiring ALS, and no effective treatment. We therefore need successful research models of ALS to help us understand the mechanism of the disease.
Several genetic faults that cause ALS have been identified from patients. We can put these same faulty genes into zebrafish, enabling us to create zebrafish that develop ALS-like features in order to help us understand the biology of the human disease. In this way, zebrafish become a powerful research model of ALS. This is possible because we share common biology with zebrafish. For example, the same genes and proteins that make motor neurons develop and function in humans also direct these processes in zebrafish.
Recently, a repetitive sequence within the genetic code of a gene called C9ORF72 has been identified as the most common cause of familial ALS. It is thought that this repetitive DNA sequence makes a toxic protein. These ALS patients have more of this repeat sequence in their genetic code than healthy people. In this project, we will create the first animal model with this significant ALS-causative mutation by making zebrafish that have different lengths of this repeat inside them. We will use this fish model of the human disease to study and understand the basic biological processes that result in motor neuron degeneration. We can then us the fish to investigate potential treatments.
MND Victoria MND Research Grant
Dr Anne Hogden
Centre for Clinical Governance, Australian Institute of Health Innovation, University of New South Wales, New South Wales
> Assessing patient cognition and behaviour in specialised MND multidisciplinary care: a feasibility study
Multiple and diverse symptoms characterise motor neurone disease (MND). In addition to physical deterioration, many patients are known to experience changes to their cognition (such as problem solving and memory) and behaviour (such as apathy). Yet, unlike physical status, cognition and behaviour are not routinely assessed in MND multidisciplinary clinical practice. The aim of this study is to improve patient care by assessing these changes, and their impact on patients and carers. We will trial a purpose- designed package of assessments to measure cognitive and behavioural change, patient wellbeing and carer burden. We will then evaluate the feasibility of these assessments for use in MND multidisciplinary clinics, and the contribution assessment results make to patient care. The insights gained from this study will: assist service planning; inform patient and carer decision-making; and allow clinicians to proactively tailor care to patients’ varied and complex needs.
MNDRIA Grant-in-aid
Dr Anna King
Wicking Dementia Research and Education Centre, University of Tasmania, Tasmania
> ALS/FTLD (frontotemporal lobar degeneration) proteins in axon function and role in disease
In the last five years there have been great increases in our understanding of the genetic basis of ALS and links have been drawn between ALS and FTLD. A number of proteins have been implicated in playing a role in these diseases. In particular one protein, TDP-43, is involved in over 90% cases of ALS. This protein is expressed in all the cells of the body and therefore its particular role in the degeneration of the nervous system is puzzling. Nerve cells are very specialised cells with a number of unique functional parts including the long nerve processes, which are responsible for transmitting the nerve signals from one part of the nervous system to another. There is accumulating evidence that TDP-43 and other ALS/FTLD associated proteins are involved in maintaining these long nerve processes. ALS is characterised at early stages by extensive loss and degeneration of nerve processes, resulting in disconnection of the motor nervous system. We currently don't know how these proteins work to maintain the nerve processes or even if they are present in them. To address this we will use genetic techniques to alter the levels of these proteins in the nerve cells and also to make them pathologic. We will then examine how these proteins are involved in the function of the nerve processes in both animal and primary cell culture models. In particular we will focus on whether they play a role in maintaining or modifying the structural cytoskeletal proteins of the axon.
MNDRA Grant-in-aid
Dr Jeffrey Liddell
Department of Pathology, University of Melbourne, Victoria
> Induction of Nrf2 by neuroprotective CuII (atsm) in SOD1-G37R astrocytes
More effective therapeutics are urgently needed for the treatment of MND. Using genetically modified mice that recapitulate the symptoms of MND, we have found that a metal complex known as CuII(atsm) elicits striking beneficial effects: the compound delays the onset and progression of symptoms and improves survival of the mice. Importantly, CuII(atsm) still elicits these disease-attenuating effects even when administered after the onset of symptoms, which is a critical characteristic for a therapeutic agent. However, it is unknown exactly how the compound is working. I have recently deduced an exciting mechanism which may explain how CuII(atsm) is acting. However, my experiments to date have been performed on cells isolated from the brains of normal mice; the compound may act very differently in cells that model MND. Thus this project seeks to determine the effect of CuII(atsm) in cells isolated from the brains of genetically modified mice that develop symptoms analogous to MND in humans. This will help determine whether this compound could be a new, more effective therapeutic for the treatment of MND. In addition, we may also learn if certain aspects are impaired in cells from these mice that may contribute to the underlying disease process.
MNDRA Grant-in-aid
Dr Marie Mangelsdorf
Queensland Brain Institute, University of Queensland, Queensland
> Targeting EphA4 as a treatment for MND
In mammalian cells a single gene can produce multiple different proteins each with a different cellular function. Around 95% of human genes produce multiple proteins in this fashion. This project will examine one gene, EPHA4 that has recently been shown to modulate disease progression in motor neurone disease (MND). We have targeted EPHA4 in a mouse model of MND and have seen a moderate effect on disease onset. Only one known protein is produced from the EPHA4 gene. Our initial analysis has suggested that there are indeed many EPHA4 proteins. This project will investigate all of the protein products produced from the EPHA4 gene, and the roles they each play in MND. EPHA4 is being targeted as a novel MND therapy and targeting all isoforms, or alternatively specifically avoiding some, may be required for effective treatment. We aim to improve targeting of EPHA4 in the development of an MND treatment.
Graham Smith MND Research Grant
Professor Pamela McCombe
University of Queensland Centre for Clinical Research, Queensland
> Investigating the consequences of increased fat catabolism in motor neurone disease
People with MND who show rapid loss of fat mass have worse disease outcome. The loss of fat mass appears to be due to the rapid use of fat as an energy source to satisfy increased energy demand from skeletal muscle. Using an animal model of MND, we will investigate the consequences of the loss of excessive fat mass. By understanding the cause and consequences of decreased fat mass we will provide essential information for the development of strategies to slow the progression of disease.
MNDRIA Grant-in-aid
Dr Diane Moujalled
Department of Pathology, University of Melbourne, Victoria
> The role of hnRNP RNA binding proteins in motor neuron degeneration
Transactivation response DNA-binding protein-43 (TDP-43) is a major constituent of the mass of protein that are characteristic of two types of brain diseases; amyotrophic lateral sclerosis (ALS) a type of MND, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), a sub-type of dementia, commonly found in patients with ALS. The mechanism by which changes in TDP-43 promote the loss of brain cell function and structure in ALS and FTLD-U remains elusive. In the current literature there is growing evidence that suggests that certain proteins referred to as hnRNPs play significant roles propagating brain diseases and are therefore considered candidates in propagating TDP-43 associated brain diseases. Our studies have shown that mutations in TDP-43 have robust effects on hnRNP expression, which may be a key factor to drive TDP-43 related brain diseases. It is well known that hnRNP proteins play a pivotal role in coordinating vital cellular processes, however, the molecular mechanism of which hnRNPs contribute to disease progression in ALS is unknown. This research aims to identify the molecular mechanism that drives changes in these proteins and reveal novel therapeutic strategies to treat clinically relevant diseases that affect the brain and spinal cord.
Charles & Shirley Graham MND Research Grant
Associate Professor Peter Noakes
School of Biomedical Sciences, University of Queensland, Queensland
> The role of altered neuromuscular signalling in ALS: factors that modify the course of MND
Despite recent advances in understanding the genetic cause of motor neurone disease (MND), the reason why motor neurones die is still unknown. In this application, we will be pursuing abnormalities in the signalling between motor neurones and muscle. This aspect of MND has not been systematically studied, and the loss of motor neurone to muscle connections is a key early event in this disease. In this study, we will collect muscle samples from MND patients and controls. These samples will be used to perform cellular and molecular analyses of nerve-muscle connections in early-diagnosed MND patients and to examine changes to gene expression in the muscle during the early stages of MND. We believe that abnormalities of the neuromuscular junction and muscle are found in MND and could be targets for development of new therapies.
MNDRA Grant-in-aid
Dr Lezanne Ooi
Illawarra Health and Medical Research Institute, University of Wollongong, New South Wales
> Examining the role of protein degradation in iPS cell models of ALS
Our major goal is to understand how and why motor neurons die in MND. Our preliminary evidence indicates that dysfunctional protein degradation and the formation of inclusion bodies are important pathogenic pathways in MND. We have found that the pathways by which inclusion bodies are formed are unique in different patients and are unlikely to cause toxicity via the same mechanism. To identify causal mechanisms of motor neuron death we need to develop robust means to interrogate the chronology of pathological events in cells from MND patients. Drawing on our recent developments in stem cell technology, we will generate and bank skin-derived induced pluripotent stem cells from MND patients. These cells will then be used to generate motor neurons that represent the complex genetic background of individual MND patients. The motor neurons will be utilised to examine the role of protein degradation dysfunction in MND pathology and neuronal death. By moving beyond mouse and other cell models currently used to study MND, our approach using induced pluripotent stem cells will be better suited to understand the complex two-hit (or potentially more) genetics that is recently coming to light in MND pathogenesis. Additionally, our novel methods of generating induced pluripotent stem cells, motor neurons and other cell types involved in MND pathology bring us a step closer to using patients’ own cells to replace those lost in this devastating disease.
MNDRA Grant-in-aid
Dr Ken Rodgers
Medical and Molecular Biosciences, University of Technology Sydney, New South Wales
> Studies investigating the non-protein amino acid BMAA, as an environmental trigger for MND
In the majority of patients with motor neurone disease (MND) no genetic cause can be identified, suggesting that environmental factors are involved. The South Pacific Island of Guam is one of the few places in the world in which a very high incidence of an MND-like neurodegenerative disease has been reported. The disease affected people from diverse genetic backgrounds living on Guam and occurred at 50 to 100 times the rate of MND in the general population suggestive of an environmental link.
We have recently demonstrated that a toxin made by blue green algae (called BMAA) and found in cycad seeds which were consumed by the people living on Guam, can be incorporated into human proteins in place of L-serine, rendering them toxic to cells. This mechanism may explain the long observed spatial association between BMAA exposure and increased risk of contracting MND.
Importantly, our recent studies also identified that the human amino acid L-serine is protective against toxicity caused by BMAA in human cells. We now wish to expand these studies to examine whether exposure to BMAA exacerbates toxicity in in vitro and in vivo models of genetic MND. Cyanobacteria are ubiquitously distributed in terrestrial, fresh water and marine environments and all five known morphological groups of cyanobacteria produce BMAA. With increasing global temperatures, human exposure to BMAA is increasing, which in turn has been linked to an increased risk for contracting MND. We propose BMAA might be a trigger for sporadic MND in susceptible individuals, thus our finding that BMAA toxicity can be blocked with serine provides clues for a preventative or therapy.
Rosalind Nicholson MND Research Grant
Dr Mary-Louise Rogers
Human Physiology, School of Medicine, Flinders University, South Australia
> A biomarker to track progression of motor neuron disease in humans and MND mice
There are no effective treatments or biomarkers to track motor neurone disease progression. We have found a protein shed from affected nerves that can be detected in urine and blood. Our aim is now to show this marker can be used to track disease in symptomatic and asymptomatic people and also mice with MND that are used to test possible new drugs. The significance of this is that a biochemical marker will be available to identify the effectiveness of new treatments for this devastating illness and to assist neurologists detect the disease much earlier than is currently possible.
Mick Rodger MND Research Grant
Associate Professor Aaron Russell
School of Exercise and Nutrition Sciences, Deakin University, Victoria
>Inhibiting microRNA-23 as a therapeutic strategy to treat motor neurone disease
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, has no cure and death from respiratory insufficiency occurs within 3-5 years after diagnosis. We identified that microRNA-23a (miR-23a) is elevated in ALS and inhibits important proteins that normally protect muscle and neurons for death. We will block miR-23a in ALS mice and expect this to prevent neuron death and significantly delay disease progression. This will provide a major advance in understanding the mechanisms involved in the development and progression of ALS and identify novel pre-clinical therapeutic strategies to prevent the development or delay the onset and severity of ALS.
Zo-ee MND Research Grant
Dr Bradley Turner
Florey Institute of Neuroscience and Mental Health, Victoria
> Therapeutic targeting of autophagy in MND
One common feature of MND is the accumulation of protein deposits inside nerve cells which leads to their death. Although the factors responsible for accumulation of these proteins deposits remain unclear, strategies that reduce the load of damaged proteins in MND represent a rational approach for potential disease intervention. We have identified a potent drug which enhances autophagy, a protective process which breaks down protein deposits inside cells. We have shown that this autophagy enhancer efficiently clears protein deposits linked to MND in the Petri dish. We propose to treat MND mice with this autophagy enhancer and predict that it will slow disease signs, preserve lifespan and protect nerve cells by reducing the burden of protein deposits in the brain. If our proposal is supported, then this study will encourage future use of autophagy enhancers for potential treatment of MND.
MNDRIA Grant-in-aid
Dr Trent Woodruff
Biomedical Sciences, University of Queensland, Queensland
> Innate immune complement signalling in peripheral immune cells during the progression of motor neurone disease
In motor neurone disease (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 the complement group of proteins. We suggest that the therapeutic targeting of complement could slow the progression of MND. In this study we will investigate this further, using blood samples from people with MND as well as animal models of MND. If this study is successful, we will then be able to perform a trial of our novel drug, which acts on this complement pathway.
MNDRA Grant-in-aid
Associate Professor Naomi Wray
Queensland Brain Institute, University of Queensland, Queensland
> Whole exome sequencing of sporadic MND
Recent studies show that genetic factors account for more than half of the risk of developing MND, even in subjects with so-called “sporadic” MND. A number of causative genes have been identified for familial MND and some of these are found in subjects with apparent sporadic MND. In some subjects there is very obvious inheritance of disease and in other families the inheritance is less clear-cut. To understand this further we need systematic studies of the genetics of sporadic and familial ALS. Local studies then need to be combined with studies from other investigators to increase power. We have a cohort of well-characterised subjects with MND, who have already been screened for the presence of the more common genes implicated in causing MND. We now wish to perform whole exome sequencing of all the genes in these patients and controls.
MND PhD Scholarship Top-up Grant for 2014 – 2016
Dr Rebekah Ahmed
Neuroscience Research Australia, NSW
> Eating, autonomic and sexual dysfunction in motor neuron disease and frontotemporal dementia
This project aims to examine the incidence and underlying causes of eating, autonomic and sexual dysfunction in motor neuron disease (MND) and frontotemporal dementia (FTD). Eating abnormalities have been well documented in FTD, this study aims to extend this work into MND. There is increasing evidence for an overlap between FTD and MND at a clinical and pathological level which has gained impetus with the recent discovery of the C9orj72 gene mutation in cases with familial FTD, FTD-MND and MND.
The term frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders characterised by shrinkage of the frontal and anterior temporal lobes of the brain. FTD presents with changes in personality and behaviour and/or progressive language problems. Change in eating patterns including reduced satiety, binge eating, increased carbohydrate consumption and stereotypic eating is a major criterion for the diagnosis of behavioral variant FTD. It is not known whether these same eating abnormalities are present in MND, but given the increasing evidence of an overlap, it is possible that they are. In FTD patients it has been found that those with eating abnormalities, have shrinkage of the posterior hypothalamus. The hypothalamus also controls the autonomic nervous system, which regulates internal bodily functions such as blood pressure control, stomach, bowel and urinary function. The hypothalamus is also involved in controlling sexual function. This project aims to examine the incidence of eating, autonomic and sexual symptoms in MND and FTD and by imaging methods and endocrine analysis examine the possible underlying causes and then possible interventions to reduce the impact of these symptoms on the quality of life of patients and carers.
Continuing grants
The following grants were awarded in previous years and continue in 2014:
MND Australia Leadership Grant 2013 – 2016
Associate Professor Ian Blair
Australian School of Advanced Medicine, Macquarie University, New South Wales
> Investigating the pathogenic basis of familial MND
There is a pressing need to develop more effective diagnostic tools and treatments for MND. To date, the only proven causes of MND are gene mutations that lead to motor neuron death. Despite recent gene discoveries, current insights have been insufficient to develop effective treatments. As part of collaborative studies, our laboratory previously made breakthroughs in MND through identification of defective genes that cause inherited forms of MND. These discoveries have opened new chapters in MND research. Despite this, the genes are yet to be identified for around 40 percent of Australian familial MND cases. More recently, our group identified further new defective genes that appear to cause familial MND. The aim of this project is to better understand the biology of MND through study of the role of these newly discovered MND genes and how defects in these genes lead to the death of motor nerves. In addition to better understanding the causes of MND, these studies should lead to development of new diagnostic tests for familial MND, and in the long-term, provide tools for investigating proposed new treatments.
The MND Australia Leadership project forms part of a new collaborative MND/ALS research program at Macquarie University, Sydney. This program brings together five research groups with strong track records in ALS and related disorders, and diverse expertise including genetics, cell biology, biochemistry, proteomics, and mouse and zebrafish disease models. This research project will foster collaboration and draw upon expertise within this program.
Ian Blair will lead this pivotal project. The MND Australia Leadership Grant will provide salary for four years for a postdoctoral research associate and laboratory costs associated with the project. Additional support will come from Macquarie University with provision of two PhD scholarships which were conditional on the award of the Leadership Grant.
Bill Gole Postdoctoral Fellowship for MND Research 2013 – 2015
Kelly Williams
Australian School of Advanced Medicine, Macquarie University, New South Wales
> Investigating the molecular basis of ALS
The only known causes of ALS are gene mutations. These account for 60 percent of familial ALS, and less than 5 percent of sporadic ALS cases in Australia. We aim to find other genetic causes of ALS using state-of-the-art genetic technologies. Discovery of new gene defects will add to existing genetic diagnostic testing in ALS families. These discoveries also provide an opportunity to investigate the causes of motor neuron degeneration in both familial and sporadic ALS, and to aid in the development of therapies. We will establish genetic variation databases to facilitate worldwide collaboration, which may also lead to the discovery of further new ALS genes.
Our laboratory, in collaboration with international ALS research groups, was instrumental in the discovery of mutations in both the TARDBP and FUS genes in ALS. These two examples highlight the importance of discovering new ALS genes to attempt to elucidate the disease mechanisms underlying ALS. However, 40% of our familial ALS cohort are yet to have a gene mutation implicated. This, and the fact that the insights gained from known ALS genes have been insufficient to allow development of effective treatments for patients, demonstrate that there are still critical genes to be identified in ALS. Each new ALS gene offers the chance to investigate its potential role in the mechanism leading to neurodegeneration. The best opportunity to discover new ALS genes will come from using next generation sequencing technologies and bioinformatics analysis of ALS families.
Graham Linford Postdoctoral Fellowship for MND Research 2013 – 2015
Dr Sharpley Hsieh
Neuroscience Research Australia, NSW
> Seeing the future in MND
This project will investigate how MND affects the cognitive domains of decision-making, semantic knowledge and autobiographical memory. The extent to which impairment in these intellectual skills is related to changes in behaviour, carer burden and patterns of atrophy will also be investigated. Findings from this study will have important clinical implications for understanding the extent to which MND patients are able to make decisions for the future, which involves knowledge about the world and the ability to draw upon a past sense of self. In addition, from a theoretical viewpoint, knowledge of the association between cognition with indices of behaviour, neuroimaging and carer burden will broaden our conceptualisation of MND as a multisystem disorder.
This project has clinical relevance to Australian health and has major theoretical implications for the understanding of MND. At a clinical level, understanding the pattern and severity of cognitive deficits in MND is critical for adequate planning and delivery of care and support for patients and their family. Importantly, findings will inform whether MND patients are impaired in their ability to plan and make decisions for the future, which involve the comprehension of complex word meanings and draws upon their past and sense of self. From a theoretical viewpoint, knowledge of the association between cognitive deficits with indices of behaviour function, neuroimaging and carer burden will add to the growing body of evidence that MND is a multisystem disorder.
MNDRA/NHMRC Co-funded PhD Scholarship 2013 – 2015
Dr Nimeshan Geevasinga
University of Sydney and Westmead Hospital, New South Wales
> Electrophysiological and neuroanatomical determination of patients with Amyotrophic lateral sclerosis with the C9ORF72 mutation
There have been significant advances made in the genetic understanding of ALS as well as another closely related condition, frontotemporal lobar degeneration (FTDL). An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of ALS and familial frontotemporal lobar degeneration (FTLD). Currently little is known about the neurophysiological/neuroanatomical and cognitive properties in patients with the C9ORF72 mutation. We wish to better characterise the peripheral nervous system function in patients with the mutation, utilising a novel threshold tracking transcranial magnetic stimulation (TMS) technique, in conjunction with neurophysiological techniques to assess peripheral nerve function. Further to this we will perform neuropsychiatric evaluations to assess the cognitive profile of patients with the affected mutation as well as undertaking neuroimaging with magnetic resonance imaging to analyse neuroanatomical patterns and relationships.
These patients will then be followed over a period of two to three years to look for changes over time. The information when gathered will help better characterise patients with this particular mutation. We will then follow these patients over time to look for changes in their neurophysiological, neuroanatomical and cognitive domains. Understanding how these genetic mutations cause motor neuron degeneration is pivotal to improving our understanding of disease pathophysiology and to the development of more powerful neuroprotective therapies.
Dr Parvathi Menon
University of Sydney and Westmead Hospital, New South Wales
> Pathophysiology of ALS: Evidence to support the dying forward hypothesis
My current research involves the use of a variety of neurophysiology techniques to understand the sequence of involvement of the motor system in MND.
Neurophysiology is the technique of recording spontaneous and induced electrical potentials in the nervous system and has been extensively used to understand the working of this system which functions as an enormous communication network in the human body and transmits information using electrical potential changes.
The nervous system is the primary target of MND which commonly affects both the peripheral aspect of the motor system comprising nerve cells and nerves supplying muscles along with the central component comprising the motor neurons arising in the cerebral cortex and their connection with the peripheral pathway. There has been long standing debate on where motor neuron disease begins: whether in the central or peripheral motor system or both simultaneously.
My research uses a variety of neurophysiology techniques to assess the central and peripheral motor pathways in order to detect alterations of function which might provide better understanding of the pattern of involvement of the motor system in MND. The ultimate aim of my research is to gain a better understanding of the unique nature of motor neuron disease and its progression so that interventions can be targeted early to where the problem begins.
PhD Scholarship MND top-up grant 2013 – 2015
Jayden Clark (PhD candidate) and Associate Professor Tracey Dickson (Principal Supervisor)
Menzies Research Institute, University of Tasmania, Tasmania
> Axonal protection in ALS
Currently the only effective treatment for ALS is the drug Riluzole, which extends a patient’s life for 3 to 6 months. Therefore there is a need for new and targeted approaches to ALS treatment.
I aim to use the drug Taxol, more commonly used in cancer therapies to prevent cancer cells dividing, to help slow progression or rescue the motor neurons from cell death. Taxol works on proteins in the axons (the long processes of neurons). These proteins help with the movement and transport of other proteins and cellular machinery through the cell. As axon dysfunction is found to be one of the earliest pathologies in ALS, a targeted approach to axonal treatment may be beneficial. This work will be done using a genetic model of ALS as well as a model of sporadic ALS currently in development in the Dickson Laboratory at the Menzies Research Institute of Tasmania. Changes to behaviour/motor function and neuronal pathology will be identified.
Rosemary Clark (PhD candidate) and Associate Professor Tracey Dickson (Principal Supervisor)
Menzies Research Institute, University of Tasmania
> Interneuron dysfunction in ALS: A new target for potential therapeutics?
ALS is a disease typically defined by motor neuron dysfunction and subsequent degeneration. However, increasing evidence suggests it may be considered non-cell autonomous, involving other neuronal and non-neuronal populations. The roles of various non-neuronal populations in ALS pathogenesis have begun to be investigated, yet a key regulatory population, the interneuron, remains largely overlooked. This is surprising as there is strong clinical evidence in both cortical and spinal regions to implicate reduced inhibition as a primary disease mechanism in ALS. Indeed motor neuron hyperexcitability precedes degeneration in many cases, suggesting dysregulation of excitatory circuitry may be a modifiable therapeutic target in ALS. I aim to explore this concept by firstly investigating pathological changes to the inhibitory interneuron populations and, secondly, by assessing interneuron vulnerability under pathogenic conditions. This will enable the role that interneurons may play in altered inhibition and disease progression to be determined.
Jennifer Fifita (PhD candidate) and Associate Professor Ian Blair (Principal Supervisor)
Australian School of Advanced Medicine, Macquarie University, NSW
> Examining the role of novel molecules causing motor neuron disease
Bill Gole Postdoctoral Fellowship for MND Research 2012 – 2014
Dr Shyuan Ngo
University of Queensland Centre for Clinical Research and School of Biomedical Sciences, Queensland
> Investigating the mechanisms underlying defective energy metabolism in motor neuron disease
Motor neuron disease (MND) is an adult onset neurodegenerative disease. In MND, the irreversible loss of cells in the brain and spinal cord causes muscle weakness, and leads to death within 3-5 years of diagnosis. To date, the cause of MND remains unknown. However, it is known that the production and use of energy is disrupted in subjects with MND. This occurs before the onset of muscle weakness and muscle loss, and may therefore contribute to the onset and further development of the disease. By understanding the cause and consequences of this change in the production and use of energy, we may be able to better understand this disease.
This project will be the first comprehensive investigation of the impact of altered energy metabolism on the pathogenesis of MND. The identification of metabolic factors that contribute to the onset and progression of MND will not only provide greater understanding of the processes that cause MND, but could lead to therapeutic interventions to correct defective energy metabolism, thereby possibly slowing disease progression, improving quality of life and alleviating the suffering of MND patients.
MNDRIA/NHMRC co-funded PhD Scholarship 2012 – 2014
MNDRIA/NHMRC Co-funded PhD Scholarship 2012 – 2014
Dr Neil Simon
Neuroscience Research Australia, New South Wales
> The distribution and spread of motor system dysfunction in early motor neurone disease
The exact nature and mechanisms of spread of the underlying pathology are currently unclear in ALS. Understanding the pathogenesis of ALS is necessary in order to develop sensitive biomarkers to permit early diagnosis of the disease, and to allow for investigation of targeted novel therapies. Currently, treatment options for ALS remain limited, in part because diagnosis is often delayed owing to diagnostic uncertainty in the early stages of the disease. The aim of this proposed research project is to clarify the pathogenic mechanisms of ALS by serial detailed clinical assessments of patients with early MND combined with novel neurophysiological and neuroimaging technologies. This research will lead to the development of optimum early diagnostic paradigms and will contribute to the search for novel targeted therapies.
PhD Scholarship MND top-up grant 2012 – 2014
Alexandra Mot (PhD candidate) and Dr Peter Crouch (Principal Supervisor)
Dept of Pathology, University of Melbourne, Victoria
> Investigating energy metabolism in models of MND to elucidate the mechanism of action of the potential therapeutic CuII(atsm)
The development of treatments for motor neuron disease (MND) is dependent on the availability of models in which to test potential therapeutics and to study the fundamental biology of the disease. The most widely used models to date involve mutations in the SOD1 gene. Our research team has demonstrated that the drug CuII(atsm) has strong protective activity in SOD1 mouse models of MND. We have recently acquired access to a new TDP43 mouse model of MND and have also tested the therapeutic potential of CuII(atsm) in these mice. Although we found some protective activity for CuII(atsm) in these mice (it potently attenuated markers of inflammation in the spinal cord tissue), the mice die prematurely due to gastrointestinal problems well before overt MND-like symptoms appear. Whether these mice represent a valid model of MND remains unclear. Through a series of in vitro experiments we have made some progress in unravelling the mechanism of action of CuII(atsm) by establishing that the compound responds specifically to conditions of impaired energy metabolism. Our current focus is on investigating the role of impaired energy metabolism in MND. By undertaking this research we expect to generate new information to help understand how impaired energy metabolism contributes to the pathogenesis of MND and to better understand the mechanisms through which CuII(atsm) is protective in SOD1 mouse models of the disease.