Great news for MND research in November 2013 with MND Australia research committee news of $1,887,483 going to twenty grants-in-aid to motor neurone disease researchers Australia-wide. Additionally, the Bill Gole Postdoctoral Fellowship has been awarded to Dr Jacqueline Leung from the Wicking Dementia and Education Centre, University of Tasmania - the fourth of 13 Bill Gole Fellowships to go to Tasmania.The Jenny and Graham Lang Collaboration Travel grant goes to Dr Rebecca Sheean at the Florey Institute of Neuroscience and Mental Health, Melbourne. A PhD top-up grant will be awarded after universities announce their new PhD scholarships in December 2013.

Congratulations to the recipients.

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.

MNDRIA 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.

MNDRIA 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.

MNDRIA 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.

MNDRIA 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.

MNDRIA 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.

MNDRIA 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.

MNDRIA 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.

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.

MNDRIA/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

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.


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