Current MNDRIA-funded research

Associate Professor Ian Blair

Australian School of Advanced Medicine, Macquarie University, NSW
 

> Investigating the pathogenic basis of familial ALS

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.

Kelly Williams

Australian School of Advanced Medicine, Macquarie University, NSW
 

> 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.

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.

Dr Julie Atkin

MND Research Group, La Trobe University, Victoria

> The role of extracellular misfolded proteins in the pathogenesis of ALS

We have exciting new evidence that

(i) the death of motor neurons occurs by the same cellular mechanism in the many diverse forms of ALS and

(ii) this mechanism leads to the spreading of disease amongst motor neurons throughout the nervous system. This proposal aims to identify how this mechanism occurs and whether a new drug we are developing can prevent the spread of pathology. Understanding these processes will enable the development of more effective therapies in the future.  

Dr James Burrell

Neuroscience Research Australia, NSW

> The impact of language dysfunction on patient quality of life and carer burden in motor neurone disease

Motor neurone disease (MND) and frontotemporal dementia (FTD) overlap significantly.

Language disturbance is a feature of FTD, and patients with MND may have similar language problems, over and above problems with speech clarity.

The impact of language disturbance in MND on patient quality of life and carer burden are currently unknown.

The present study, using state of the art imaging techniques, aims to detect and characterise language dysfunction, as well as determine the brain structures involved in language dysfunction, in patients with MND. The impact of language dysfunction on the lives of patients and carers dealing with MND will explore and be used to develop relevant interventions to improve patient quality of life and carer burden.  

Associate Professor Tracey Dickson

Menzies Research Institute, University of Tasmania

> Interneuron dysfunction in amyotrophic lateral sclerosis: A new target for potential therapeutics?

Amyotrophic lateral sclerosis (ALS), the major cause of motor neurone disease, is a devastating disease for which there is no cure. Our research group has new evidence that suggests that ALS may be caused by the dysfunction of a particular type of nerve cell called an interneuron which has an important job in neuronal communication in the brain and spinal cord. Using a range of experimental approaches that we have developed in our lab, we will determine the pathological changes that characterise interneurons in ALS and investigate interneuron vulnerability to disease-specific insults.

Collectively this work will increase our understanding of the cause of ALS and will potentially reveal new targets for developing a treatment or cure.

Dr Robert Henderson

University of Queensland Centre for Clinical Research

> Use of biomarkers to understand ALS

Amyotrophic lateral sclerosis (ALS) is a severe progressive disease associated with death of upper motor neurones in the brain and lower motor neurones in the spinal cord.

One approach to developing therapies is to understand what factors influence the progression of disease, with the eventual goal of augmenting factors that improve the outcome. However, there is difficulty in measuring the underlying disease process in ALS. We have developed a novel neurophysiological technique to assess the numbers of motor units in muscle, an advanced MRI method to assess the upper motor neurones and a blood biomarker of axonal loss.

This project will investigate ways of measuring the loss of motor neurones in human subjects with motor neurone disease and will also investigate factors that influence the rate of loss of these cells. Understanding of these factors could indicate ways to treat the disease.

Dr Anna King

Menzies Research Institute, University of Tasmania

> Axonal protection in ALS

ALS is characterised by degeneration of the nerve processes that stimulate the muscle tissue as well as loss of nerve cells in the spinal cord and brain. One reason that current therapeutics for ALS may not have been successful is that although they may protect the nerve cell they may not protect the nerve process from degenerating. We have developed a mouse model that involves exposing the nerve cells in the spinal cord to toxins that are thought to mimic the conditions of ALS. This causes the nerve process to degenerate and die back from the muscle as well as loss of the nerve cells, making this model an ideal candidate for testing therapeutic agents. We have preliminary data from cell culture studies suggesting that we can protect nerve processes from degenerating by stabilizing their cytoskeleton using taxol-like agents. Taxol is currently used in the treatment of cancer and is thus approved for human use. Taxol has also been shown to reduce pathology in models of Alzheimer’s disease. We will test a taxol-like agent, epothilone, in our ALS degeneration model to determine if it is able to rescue the nerve processes from degeneration.

Epothilone is capable of passing the blood brain barrier and can target neurons throughout the nervous system. If successful we envisage that these drugs may be used as a treatment for ALS either alone or in combination with therapeutics that protect the nerve cells.

Professor Pamela McCombe

University of Queensland Centre for Clinical Research

> Investigating the causes and consequences of growth hormone dysfunction in motor neuron disease

People with MND show severe loss of weight. This is partly due to increased metabolism of muscle.

We will investigate the causes of this, using an animal model.

Understanding the cause of this increased metabolism is necessary so that possible strategies to overcome this problem can be developed, with a view to slowing the progression of disease.

Professor Grant Morahan

Centre for Medical Research, University of Western Australia

> Discovery of novel genes protecting against motor neurone disease

The cause of 20 percent of cases of inherited motor neurone disease is a mutation in a gene known asSOD1. Some people with mutations in SOD1 do not develop the disease or develop it much later in life. We propose that there are other genes that influence when a person will get MND. It is extremely difficult to identify these genes directly in humans. However, we can use a powerful new system we have developed using intensively characterised mouse genetic models to find these genes.

Finding genes that can protect against the development of MND will give us a better understanding of its causes and we will be better placed to develop new ways to treat this disease.

Professor Garth Nicholson

ANZAC Research Institute, University of Sydney

> Finding new MND gene variants

Just like cancer, the underlying cause of the fatal disorder, motor neurone disease, is often the result of disease-causing gene variations. And just like cancer, most cases of MND are not obviously inherited. And as in cancer, understanding the mechanisms and interactions of MND gene variations will help find what is causing the disease. These gene variations provide targets that will allow selection of therapeutic molecules for MND drug treatment trials.

This proposal aims to find these toxic gene variations as a necessary first step for developing treatments in MND.

Dr Mary-Louise Rogers & Professor Robert Rush

Flinders University, South Australia

> Biomarker for determining outcomes of motor neurone disease treatments in animal trials

There is no effective treatment or way of monitoring treatment for motor neurone disease.

We have identified a protein in urine of a mouse model of MND that is also present in humans with MND. In this project we will investigate if the protein can monitor disease progression in the pre-clinical testing of treatments. The project incorporates our immunogene technology to test the agent as a potential drug for the treatment of MND in mice. Successful outcomes will encourage the use of our biomarker in trials of treatments for MND in humans.

Dr Tony Roscioli

School of Women’s and Children’s Health, Sydney Children’s Hospital

> Genetic diagnosis and gene discovery in motor neuron diseases

It is likely that the majority of motor neuron diseases have a genetic basis, however gene mutations have not been defined in most patients. To date the sequential testing of single genes has been slow and expensive and genetic mutations in most affected people remain to be identified. The recent improvement of gene testing technology has allowed diagnostic testing of all genes simultaneously (called Next Generation Sequencing or NGS).

The present project aims to further elucidate the genetic and pathophysiological mechanisms leading to motor neuron diseases, together with clinical assessments of the various presentations. The application of NGS in patients with various motor neuron diseases is expected to lead to a greater proportion of patients with a defined genetic basis for their disease and also the discovery of novel genes for these conditions.

Further identification of the genetic origins of the motor neuron diseases may provide new opportunities to understand the biology of normal and diseased motor neurons, which will thereby accelerate the development of future treatment approaches. In addition, NGS for motor neuron diseases will be significant in establishing early, specific and widely accessible diagnostic methods, which in turn may enable earlier access to forms of treatment to delay or prevent disease onset.

A health economist will examine whether NGS is a viable, rapid, high-yield and cost-effective alternative or adjunct to current sequential investigations.

Dr Rachel Tan

Neuroscience Research Australia, NSW

> Are polyglutamine repeats the mystery proteins in the novel p62 lesions in motor neurone disease?

The recent identification of novel p62 inclusions in the brains of patients with MND and the new C9ORF72 gene abnormality suggests that there are additional proteins involved in the degeneration occurring in MND, and that these proteins have a much broader affect on the nervous system.

The p62 protein labels other proteins for degradation in cells. It will be important to identify the labelled protein to determine what cell pathways are involved.

It was recently identified that variability in another gene, the ataxin-2 gene, can produce slightly longer ataxin-2 proteins due to increased polyglutamine repeats, and that people with this variability are much more likely to get MND. In other research it has been shown that p62 binds ataxins and contributes to assembling them for degradation. People with very long ataxin proteins (some with MND) get degeneration in the cerebellum and spinal cord.

Based on the distribution of the novel lesions in the cerebellum of MND patients, and knowledge that p62 binds ataxins, we will investigate if the mystery protein in the novel p62 inclusions is ataxin-2 with increased polyglutamine repeats. Identifying the mystery protein involved in these novel lesions in MND will identify the cellular pathway that is abnormal, which can then be targeted for therapeutic treatment.

Dr Lachlan Thompson

Florey Institute of Neuroscience & Mental Health, Victoria

> Generation of spinal motor neurons from stem cells and transplantation in an animal model of MND

Unlike other parts of the body, the nervous system has a very poor capacity to repair itself. This means that damage, e.g. through the neurodegenerative process that occurs in motor neurone disease (MND), is irreversible and has permanent functional consequences for the patient. Most of the experimental therapies under development are protective strategies that aim to stop or slow the on‐ going disease process but do not in any way address the damage that has already occurred. There is thus a tremendous need for the development of restorative treatments that are capable of reversing the impairments caused by the disease. Stem cells are seen as having significant potential in this context.

The basic idea behind a stem cell-based treatment for MND is that new neurons grown from stem cells in the laboratory can replace those lost to the disease after transplantation into the patient. Our recent work in this area shows that these neurons have a remarkable capacity to integrate into the host brain after transplantation. The aim of this project is to assess the therapeutic impact of this approach in an animal model of MND and to identify potential hurdles in the development of successful stem cell‐based therapies for MND.

Dr Bradley Turner

Florey Institute of Neuroscience & Mental Health, Victoria

> Autophagy dysregulation in MND

MND is characterised by accumulation of damaged proteins inside nerve cells. This may arise from defects in cell quality control. We have identified that a quality control process inside motor neurones called ‘auto-phagy’ (literally meaning self-eating), which allow cells to cannibalise and renovate themselves is abnormal in petri dish models of MND. We now wish to determine how early this defect arises in a mouse model of MND and whether stimulating this compartment can improve the disease course. If our idea is supported, then autophagy presents a new disease player in MND and potential target for treatment strategies.

This project builds upon our previous research funded by the MNDRIA and seeks to determine the role of autophagic dysregulation in the pathogenesis of MND.

Associate Professor Anthony White

Department of Pathology, University of Melbourne

> The role of RNA-binding protein hnRNP K in motor neuron degeneration

There is currently little understanding of how changes to TDP-43 result in motor neuron degeneration in ALS. While mutations to TDP-43 are known to result in disease and this involves altered cellular localization of TDP-43 in affected neurons, the consequences of this remain unknown.

Our studies have found key interactions between TDP-43 and hnRNP K, a nuclear and cytosolic RNA-binding heterogeneous ribonucleoprotein. We have also shown that mutations in TDP-43 have robust effects on hnRNP K expression and phosphorylation in motor neuron cells. It is well known that hnRNP K is a pivotal RNA-binding protein that co-ordinates extracellular signals with intracellular signaling pathways and RNA processing events. Studies have also shown that hnRNP K has a key role in many diseases including neurodegeneration.

This is the first study to specifically investigate the role of altered hnRNP K processing in ALS. We will determine how mutations to TDP-43 affect hnRNP K expression, phosphorylation, and localization. We will also examine how these changes to hnRNP K processing affect its key role in regulating mRNA expression during neuronal cell stress.

The results obtained in this study will provide a valuable insight into how mutant TDP-43 induces detrimental changes to RNA processing resulting in motor neuron cell loss. These studies may provide the basis for future investigation into novel drug targets for treatment of ALS.

Professor Mark Wilson

University of Wollongong, NSW

> Protein aggregation and chaperones: key players in MND

Current evidence strongly suggests that inappropriate aggregation of protein molecules is a primary contributor to motor neurone disease pathology. However there is very limited understanding of the molecular processes involved or of the role of chaperones (the usual defense against protein aggregation).

We have developed techniques to physically isolate pure protein inclusions from the cytoplasm of MND patient spinal cords and engineered cell models and have commenced analysis of these inclusions to identify their constituents. The inclusions are implicated in MND pathology and their composition may give clues as to the specific mechanisms contributing to motor neurone cell death and disease. We have also shown that the chaperone, clusterin, protects against loss of locomotor activity and extends life in transgenic Drosophila expressing TDP-43 (a major component of MND inclusions).

Clusterin also co-localises with TDP-43 both in human MND patient spinal cord sections and in cells over-expressing TDP-43. This project will determine

(i) the relative abilities of different chaperones to inhibit the aggregation of TDP-43, and

(ii) those elements (including chaperones) that most critically impact upon nerve cell activities and viability. In summary, this project will provide quantum advances in understanding of the cellular and molecular processes that underpin the development of MND and has the potential to pioneer new directions in MND diagnosis and therapy.

Dr Nimeshan Geevasinga

University of Sydney and Westmead Hospital, NSW

> 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, NSW

> 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.

Jayden Clark (PhD candidate) and Associate Professor Tracey Dickson (Principal Supervisor)

Menzies Research Institute, University of 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.

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.