Research reports 2016

These progress reports outline how donors' gifts have been put to work to advance understanding of MND and take us closer to finding an effective treatment. 

MND Australia Ice Bucket Challenge grant

Professor Naomi Wray
University of Queensland

Sporadic ALS Australian Systems Genomics Consortium (SALSA-SGC)

The SALSA-SGC grant aims to collect consistent longitudinal clinical and biological samples across all clinics in Australia, with a long-term goal of generating and analysing systems genomics data from biological samples collected from affected individuals over several time points.
We have made significant progress in this project in coordinating and commencing training in the use of the SALSA protocol at all seven clinical research sites. We continue to make good progress in the area of research governance specifically Human Ethics with four sites receiving HREC approval for data and biological sample collection. NSW and SA made amendments to their ethics approvals to commence collection in early 2017.
We have designed a bespoke, secure, online platform for the management for the collection of demographic and clinical data, and the tracking of biological samples collected. The initial basic set of clinical variables to be collected has been agreed upon by the majority of clinicians involved in this project. The online data entry system is already operational in the Brisbane and Victorian clinics. Training has been conducted in Victoria, South Australia and Western Australia to allow sites to become operational post-ethics approval. We also conducted an intensive two-day training course in October 2016 in Brisbane where all research coordinators from the clinical sites attended. Biological sample collection protocols have been developed and disseminated across all sites.
The project manager is in frequent communication with all clinical sites ensure progress of SALSA.

Betty Laidlaw MND Research Grant (2016 – 2018)

Dr Peter Crouch
University of Melbourne

Copper malfunction in motor neurone disease: a therapeutic target for sporadic MND.

After the first 6 months of this 3-year project we have successfully set in place many of the things needed to complete the work we proposed to undertake: we have recruited staff, obtained new human tissue samples, expanded our mouse colonies in preparation for up-coming drug testing, and have acquired fundamental consumables used in the lab.  

On the research productivity front, the best progress made thus far has been on the analysis of human brain and spinal cord tissue. The over-arching objective of this project is to continue to strengthen the link between sporadic MND and the drug that we have developed and tested in animal models of familial MND (copper-ATSM).  By analysing brain and spinal cord tissue from cases of sporadic MND, our understanding of our drug’s therapeutic relationship to sporadic MND continues to grow. We are achieving this by performing more comprehensive biochemical assessments of copper and copper-dependent processes in human tissue and by analysing tissue obtained from a larger number of cases. Copper-ATSM is now being tested in Australian MND patients. These initial clinical studies are being performed primarily to ascertain the drug’s safety and tolerability. The information that we’re currently generating in the laboratory will help us move towards the next phases in the clinical testing process – the phases in which copper-ATSM can be tested for its therapeutic activity.


MND Australia Leadership Grant

Associate Professor Ian Blair
Macquarie University

Investigating the pathogenic basis of familial ALS

As a four-year award, the MND Australia Leadership grant offered an opportunity to extend beyond the normal short-term goals, to undertake strategic research with longer-term outcomes. The primary goals were to identify genetic cause and risk factors for MND. These provide a window to understand why motor neurons degenerate in MND and clues to where diagnosis and therapeutics may be targeted. They also enable gene specific therapies to be developed and IVF technology to ensure that faulty genes stop at this generation. We also sought to understand what genetic factors contribute to sporadic MND, and those that lead to longer survival or later onset among ALS family members.

Longer-term funding enabled us to build a research framework, with patient recruitment, research training and infrastructure. This increased our capacity for strategic research, to lead our genetic studies but also to generate genetic data for Australia’s role in large-scale international research consortiums. These include the International Familial ALS consortium and Project MinE, the largest genetic study ever attempted in sporadic MND. 

The outcome of these studies include discovery of 8 new MND genes in the past four years, including ERBB4, SS18L1, OPTN, TUBA4A, TBK1, CCNF, SFPQ, C21orf2 and NEK1. Several of these have translated into new diagnostic tests for familial MND. Indeed, our Australian led research found that CCNF mutations are responsible for disease in a subset of MND families from Australia, Canada, Spain, Italy, Japan, the UK and USA. We have now developed cell and animal models based on mutant CCNF that are available to understand the biology of motor neuron death and to assess new therapeutic strategies for familial and sporadic MND. This research resulted in over 25 original research publications published in international scientific journals. Almost 50 scientific presentations were made at local, national, and international scientific conferences.

These research endeavours and outcomes have helped to build research capacity. For example, the data from our publications helped support successful grant applications to the National Health and Medical Research Council of Australia that have secured employment for research staff and ongoing research projects for coming years, increasing and accelerating our research output. It further supported in part, the MND studies of five PhD students (three completed, two continuing) and three Masters students (all completed), all but one have continued with MND research. This grant also supported in part, the genetics and genomics program that was a catalyst for establishment of an MND research program at Macquarie University. This culminated in 2017 with formal recognition as the “Macquarie University Centre for MND Research”, which now comprises over 70 research staff and students dedicated to MND research and the Centre’s goal, to solve MND. Associate Professor Blair is the Centre Director.


Postdoctoral fellowships

Beryl Bayley Postdoctoral Fellowship

Dr Michelle Farrar
The University of New South Wales

Motor neurone diseases in children and young people – understanding pathophysiology and developing treatment approaches

Studies understanding disease progression, developing outcome measures and the impact of illness in children and young people with motor neurone disease are ongoing. In addition, clinical trials of potential new therapies are continuing. Interim analysis of a phase 3 clinical trial has generated promising and statistically significant results such that the study has been stopped and all patients moved to an open label extension study. Consequently, an Expanded Access Programme has been established. Taken together these studies endeavor to facilitate the development of therapies and create strategies to determine their impact for children and young people with motor neurone disease.

Bill Gole MND Postdoctoral Fellowship 

Dr James Howells 
University of Sydney

Hyperexcitability of the lower motor neuron in ALS

Motor units consist of a lower motor neuron and the muscle fibres that it innervates. They are the building blocks of the neuromuscular system.  Motor units are the final common pathway for delivering voluntary and reflex movements. The loss of motor neurons in ALS leads to the re-innervation of denervated muscles fibres by the surviving motor axons.  Our hypothesis is that the excitability of re-innervated motor units is altered, and that this may provide a peripheral mechanism for selective vulnerability of lower motor neurons.

Our results support the hypothesis that the excitability of large single motor units is altered, with an increase in their excitability compared to recordings from normal controls.The mechanisms underlying this hyper-excitability are complex, but previous studies have pointed to a down-regulation of potassium channels, and an up-regulation of a particular type of sodium channel. Mathematical modelling suggests that the altered excitability is due to an inability of nerve fibres to maintain ion channel expression.


Collaboration grants-in-aid

Graham Stanford MND Collaboration Grant

A/Prof Tracey Dickson
Menzies Institute for Medical Research, University of Tasmania

Inhibitory dysfunction in the Cortex: Tackling MND from the top down
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 have new evidence that ALS may initially be triggered by the death or dysfunction of a particular type of neuron in the brain – the interneuron. We are developing new models for understanding this process. We have made excellent progress developing our in vitro models and will be commencing our in vivo investigations in the next six months. If our hypothesis is proven correct, translation to the development of a therapeutic would be rapid with many modulators of inhibitory function already available for preclinical testing.

Jenny Barr Smith MND Collaboration Grant

Dr Peter Crouch
University of Melbourne

Drug-specific biomarkers to facilitate clinical translation of CuII(atsm) as a potential therapeutic for MND

Our team has developed the compound copper-ATSM as a potential treatment option for MND. As we enter the clinical testing process it will be beneficial to have biomarkers that can be used to monitor copper-ATSM after it has been administered to people with MND. Biomarkers are proteins and/or metabolites present in accessible fluids (such as blood) that change in response to the disease or a drug. The aim of this project was to identify biomarkers that may be used to monitor copper-ATSM during clinical testing. To address this aim we collected biofluids from people with MND as well as from animals, which we treated with copper-ATSM. The analyses we have conducted to date have generated some very promising initial outcomes and we anticipate we will be able to monitor copper-ATSM via analysis of patient biofluids. Our focus now is to validate our initial findings and to identify the biomarkers that provide the clearest indication of the therapeutic activity of copper-ATSM.  

Cure for MND Collaboration Initiative Grant

Dr Bradley Turner
Florey Institute of Neuroscience and Mental Health, University of Melbourne

A synergistic approach for treatment of MND using neurotrophic and gene therapy

MND is a complex disorder caused by many factors and is likely to require multiple treatments targeting different aspects of the disease. In particular, defects in gene splicing and loss of motor neuron connections to muscle are two main pathological events implicated in MND. This project seeks to evaluate the effectiveness of a new "gene therapy" which aims to correct gene splicing and promote regeneration of motor neuron connections.

We have shown that our novel gene therapy agent can cross from the bloodstream into the spinal cord and very efficiently target motor neurons in mice, the affected cell type in MND. Importantly, our gene therapy reaches all motor neuron populations in the spinal cord. Lastly, our gene therapy agent leads to sustained targeting of motor neurons up to a week. These results provide proof-of-principle that our gene therapy agent enters the central nervous system and can broadly and effectively target motor neurons from the periphery. We have also established the optimal treatment dose and timing of administration of our gene therapy, which will guide future studies in animal models of MND.



MNDRIA Grant-in-aid

Dr Catherine Blizzard
Menzies Institute for Medical Research, University of Tasmania

Investigating synaptic dysfunction in ALS

There is growing evidence that neuronal dysfunction in the cortex is occurring in ALS well before symptoms present. 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. We have established new mouse models to investigate how defective function of TDP-43 alters synapses and nerve cell communication and how these changes lead to the nerve cell death that charaterises ALS. Furthermore, we have now identified that dendritic spine turnover is region specific, with the motor cortex having an increased rate of new spine growth. Understanding how this increased spine turnover, and potentially demand for plasticity, affects neuronal function in the motor cortex may be key in elucidating why this region is so vulnerable to dysfunction in ALS.

MNDRIA Grant-in-aid
Professor Elizabeth Coulson
School of Biomedical Sciences, University of Queensland

Regulation of neurotrophin signalling as a treatment for MND

This project is testing whether a candidate therapeutic approach, previously shown to have some benefit in MND model mice, can have improved benefit when administered earlier and directly to motor neurons in the MND mouse model. Such knowledge is required to determine whether our therapeutic approach is efficacious enough to be further developed for humans with MND. 

Our therapy entails provision of our “drug” called c29, through genetic means. This requires us to breed MND model mice to mice that can make c29 in motor neurons via a complex transgenic mechanism, which is a lengthy process (several generations of mice breeding is required to obtain the mice appropriate for our experimental analysis of the treatment). Therefore, we will not know the outcomes of the “treatment” until when we have sufficient numbers of the requisite mice, matured past the age that the animals usually develop MND symptoms; preliminary results should be available later in the year.

zo-ee MND Research Grant

Dr Peter Crouch
University of Melbourne

Proteomic investigation of functional copper deficiency in MND: Implications for Cu(atsm) as a novel therapeutic

Our bodies need copper. This is because many of the proteins in our body require copper for normal functionality. Prior to starting this project we had discovered that brain and spinal cord tissue collected from people who had MND does not contain sufficient copper to sustain normal function. The aim of this research project was to obtain a more comprehensive understanding of which copper-dependent proteins are affected in sporadic MND. This type of information can be gained one of two ways: you can predict individual copper proteins to investigate then use experimental methods tailored to those proteins, or you can use experimental methods that enable the measurement of many proteins simultaneously. For this project we used the latter of these two approaches. The outcomes that we have generated have provided us with a broader understanding of the extent to which important copper-dependent processes fail in MND. Moreover, the outcomes we have generated from this project have given us new insight to why these copper-dependent processes fail. It is expected that our broader understanding of copper malfunction in MND will provide further support for our drug copper-ATSM and thereby facilitate its progression through the clinical testing process.

Jenny Simko MND Research Grant

Associate Professor Tracey Dickson
Menzies Institute for Medical Research, University of Tasmania

Inhibitory dysfunction in ALS: a systematic human pathology analysis

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 excitotoxcity. We have new evidence that ALS may initially be triggered by the death or dysfunction of a particular type of neuron in the brain – the interneuron. We have started to perform a detailed examination of the density of particular interneurons in human ALS tissue. We have already received a small number of tissue samples from the Australian Brain Bank network and we are investigating regions of the brain that are affected in MND (the motor cortex) and also other spared regions (the somatosensory cortex). Using these cases we have optimized labelling for three interneuron subclasses – NPY expressing cells, Calbindin cells and Calretinin cells. We have found that in MND tissue there are particular interneuron subsets affected whereas others show a potentially neuroprotective response. Based on this exciting preliminary data and now that labelling protocols have been established we will perform systematic pathological analysis in a much larger unique set of human post-mortem ALS tissue, sourced through the Oxford Brain Bank and the Australian Brain Bank Network. Our experiments will determine if interneuron pathogenesis precedes, and therefore could be a trigger for, motor neuron pathology and cell death in the cortex and/or the spinal cord, causing MND. 

Peter Stearne Familial MND Research Grant

Dr Nimeshan Geevasinga
University of Sydney

Pathophysiological and diagnostic biomarkers of familial and sporadic amyotrophic lateral sclerosis

To this day, there is no consensus as to where ALS begins and how it progressively spreads. We are particularly interested in a genetic form of ALS, the c9orf72 gene expansion, which is the most common cause of familial ALS.  We will study healthy carriers with this gene mutation, in addition to sporadic ALS cases and follow them over a five-year period. We will be using specialised neurophysiological and MRI tests to evaluate these patients and we hope to localise where the initiating problem with ALS patients may start. Over time, we hope to use these neurophysiological tests as ‘biomarkers’, tests which can be repeatedly performed over time, giving us an insight into how the disease progresses over time. Furthermore, there is promise that new therapies in the future may be helpful in ALS. 

MNDRIA Grant-in-aid

Dr Albert Lee
Macquarie University

Identifying mechanisms responsible for ubiquitination of TAR DNA-binding protein 43 (TDP-43) in ALS pathogenesis

Despite the mechanisms being poorly understood, it has been postulated that the formation of TAR DNA-binding protein 43 (TDP-43) protein aggregates is a key step in ALS pathogenesis. We have recently identified mutations in a new ALS gene (CCNF) that encodes a protein (cyclin F) involved with protein degradation. We have clear evidence to indicate that cyclin F physically associates with TDP-43 to form inclusions within neuronal cells. This project aimed to determine whether TDP-43 was a putative substrate of cyclin F and to what effect does this interaction causes TDP-43 accumulation and impairment in neuronal cells.

Cure for MND Foundation Research Grant

Dr Peter Noakes 
School of Biomedical Sciences, University of Queensland 

Exploiting the opposing actions of complement receptors C3aR and C5aR1 in the treatment of MND

The immune system defends us from infection. One major part of the immune system is the complement cascade. In this project, we have been looking at two complement proteins C3a and C5a. We have been able to show that C3a may protect motor neurons from death, while C5a acts to accelerate motor neuron death.  For C3a, we have shown in MND mice lacking C3a’s receptor mice show worse MND symptoms – suggesting if we can activate its receptor (C3aR) it will provide a protective effect. We are now in the development of new drugs that will activate C3a’s receptor C3aR. For C5a we have now shown in two MND models that if we block its receptor (C5aR1), with our drug PMX205 it will delay MND symptoms, including muscle inflammation. PMX205 is now progressing into clinical trials.

MND Ice Bucket Challenge Grant

Dr Susanna Park
University of Sydney

In vivo markers of ALS disease activity – linking structure to function 

This study aims to examine how best to measure disease activity and progression in ALS, an important step in the development of prognostic markers for the clinical setting. We will utilise a range of assessment tools – particularly assessment of cortical excitability and imaging of cortical metabolism – to link these markers to disease activity in ALS. Patient recruitment has now commenced and 20 patients have been recruited to date, following some delays in the ethics and governance approval processes. In the interim, we have conducted a follow-up analysis of 189 ALS patients to determine the impact of cortical function on markers of disease activity in ALS, which has been published in a scientific journal. 

Cure for MND Foundation Research Grant

Dr Mary-Louise Rogers
Flinders University

Development of novel Immunogenes to improve growth factor support for motor neurons

We have developed a technology called immunogenes that enable delivery of therapeutic genes into the nerves affected in MND from the circulation. This technique uses blood proteins called antibodies to deliver genes specifically to motor neurons. In the past six months we have shown the dosing needed to deliver immunogenes to 60% of newborn mice motor neurons. We have also incorporated glial derived growth factor and insulin-like growth factor genes into our gene delivery system. The next stage is ensuring we can deliver these growth factors in vitro and to motor neurons newborn mice using our immunogenes.

Neale Daniher MND Research Grant

Dr Darren Saunders
University of NSW

Ubiquitin depletion as a cause of Amyotrophic Lateral Sclerosis 

A hallmark of ALS pathology is the accumulation of large “clumps” or aggregates of ubiquitin-tagged proteins within motor neurons. We have made significant progress towards mapping changes in protein modification in cells from ALS patients. Our new data supports the highly novel hypothesis that disruption in ubiquitin balance within cells is an underlying cause of ALS. This predicts that increasing the availability of ubiquitin in motor neurons will be protective regardless of the underlying genetic basis for disease. We hope to continue collecting data to support this prediction, focusing on functional experiments to directly test the proposed model. This research will result in a fundamental shift in our understanding of ALS pathogenesis, and is providing validation of a highly novel potential therapeutic strategy to rescue dying nerve cells. We will continue with functional experiments using gene therapy to directly measure the ability of recalibrating the ubiquitin balance to protect nerve cells from toxicity induced by ALS gene mutations 

Cunningham Family MND Research Grant

Dr Frederik Steyn
Univeristy of Queensland Centre for Clinical Research

Metabolic and gut dynamics in MND: Identifying novel strategies to meet energy needs in patients

This project sought to determine whether a change in gut bacteria might occur alongside changing energy needs in MND. We collected data to match the energy intake and use of study participants with the composition of their gut bacteria. Results show a change in the diversity of gut bacteria in some MND patients. The cause for this difference remains unknown, but it might be due to changes in eating behaviour or the body’s response to MND. We are conducting ongoing statistical analysis, and are expanding studies to collect more samples. Results may provide new insights into disease processes specific to MND, while improving our understanding of why some patients have higher energy needs. 

Cure for MND Foundation Research Grant

Dr Lachlan Thompson
Florey Institute for Neuroscience and Mental Health

Towards cell-based therapies for MND: identifying and tackling practical challenges in pre-clinical research

Our studies are aimed at developing stem-cell based therapies for MND. One of the challenges we are faced with in the progress of these therapies is the rejection of implanted cells by the recipient’s immune system. We have determined that a particular drug can prevent this rejection, and importantly, this drug does not negatively impact the disease progression of MND. We now hope to use this drug to prevent the rejection of donor cells in animal models of MND, so that these cells can integrate into the nervous system and possibly lead to increased motor performance or lifespan in these animals. It is possible that success in these preclinical studies may lead to treatments for MND based on the implantation of stem-cells.

Cure for MND Foundation Research Grant

Dr Adam K. Walker
Macquarie University

Pre-clinical therapeutic testing and biochemical changes associated with neuron survival in a validated TDP-43 mouse model of MND

In this project, we have used newly developed genetically modified MND mice to test therapeutics and to analyse the biochemical changes that occur over time in disease. The aim of these studies is to identify new ways to treat MND. In one set of experiments, we tested drugs on MND mice to find new treatments. These studies are ongoing and will be completed in late 2017. We hope to identify drugs that are more effective than riluzole in the MND mice, which can then be progressed to human studies. In a second set of experiments, we have profiled the protein changes in brain and spinal cords of MND mice before symptom onset, after symptom onset and at a late stage of disease. We have identified more than 240 proteins that are either highly increased or decreased in MND mice. Excitingly, our studies have revealed both known changes related to MND (validating the approach we have used) as well as new biochemical pathways not previously implicated in MND. These unknown biochemical pathways offer new avenues for developing disease-specific approaches for therapeutics, which we are investigating further.

MNDRIA Grant-in-aid

Dr Shu Yang
Macquarie University

Ubiquitin Proteasome System dysfunction as a biomarker for the diagnosis and prognosis of motor neuron disease 

The existing tools for diagnosing and monitoring MND disease progression are poor. The aim of this proposal is to investigate the possibility of using readily available MND patients’ fibroblast cells as a platform to facilitate diagnosis and prognosis. Based on our preliminary studies, we hypothesise that imbalance between protein synthesis and degradation is a common biomarker in all MND cases. With the assistance of this grant-in-aid, we have optimized assay protocols as well as begun the collection of additional MND patient fibroblast cells to obtain sufficient lines to test our hypothesis. This study will allow us to assess a new biomarker to assist MND diagnosis. It will also provide insights into MND pathogenic mechanisms and facilitate further grant application. 

NHMRC/MNDRIA Co-funded Postgraduate Scholarship

Nicole Sheers
Institute of Breathing and Sleep, Austin Health

Lung volume recruitment in neuromuscular disease: Can ‘breath-stacking’ improve lung function, respiratory symptoms and quality of life for people with neuromuscular disease?

Since 2015, we have been undertaking research to investigate whether performing particular breathing exercises every day for three-months improves people’s breathing function, cough effectiveness and quality of life. Thirty-four people have participated so far, and we are still seeking volunteers.

Eighty-seven percent of people decided to continue with a form of breathing exercise after their study involvement finished. It is expected that at the end of this research project we will have information to help people living with MND decide whether to incorporate regular respiratory exercises into their clinical care or not.


MNDRIA PhD Scholarship Top-up Grant

Dr Rebekah Ahmed
Neuroscience Research Australia and Brain and Mind Centre

Eating, autonomic and sexual dysfunction in FTD and ALS

There is increasing evidence for an overlap between FTD and MND at a clinical and pathological level. Change in eating patterns including reduced satiety, binge eating, increased carbohydrate consumption and stereotypic eating is a major criterion for the diagnosis of behavioural variant frontotemporal dementia (bvFTD) and is present in over 60% of FTD patients. Previously, research into this area has relied on carer reports. This is the first study that has aimed to observe the eating habits of FTD patients in a test meal approach and to examine the effects that these eating changes have on metabolism. In MND, there is increasing evidence that metabolic changes may affect disease progression, with factors such as hyperlipidemia and insulin resistance being protective. In FTD, we have established that there are similar metabolic changes affecting cholesterol and insulin levels to those seen in MND. This raises the possibility that these factors may also be protective in FTD, and offers the potential to examine specific interventions to modify metabolism to affect prognosis.

Dr Thanuja Dharmadasa
Brain and Mind Centre, University of Sydney

Motor Neurone Disease: site of onset and patterns of disease spread

This clinical study uses clinical and multimodal investigations to assess patients with MND over the course of their illness. Over the last six months, approximately 30 newly diagnosed patients have been prospectively recruited for the study. These patients have all undergone detailed clinical assessment, nerve studies, cognitive assessment, genetic testing, as well as brain and nerve imaging. New patients will continue to be recruited over the next year, and all patients will be seen every 3–4 months. 

Through this research, we hope to significantly increase understanding of the patterns of this disease, and develop suitable biomarkers to differentiate the subtypes of MND. For people living with MND, this research will enable an earlier diagnosis, improve patient assessment and management, identify the initiating site, predict spread of disease, and thereby provide a more accurate prognosis. This overall insight will ultimately contribute to advancing the development of new treatment strategies.

Dr Jennifer Fifita 
Faculty of Medicine and Health Sciences, Macquarie University

Examining the role of novel molecules causing motor neuron disease

Genetic mutations account for 60% of familial MND cases, and approximately 5% of sporadic cases in Australia. In my PhD, I sequenced the entire exome (all the genes) of five Australian MND families and identified possible MND causing gene mutations for each family. Subsequently, I analysed each candidate variant to predict its potential to cause problems that could lead to MND. I then focused on a single exciting candidate, and carried out studies to understand its specific function in MND. Identifying causative mutations helps to develop diagnostic testing for people with familial MND, and also provides insights to sporadic MND.

Emily McCann
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University

Investigating the genetic and epigenetic basis of amyotrophic lateral sclerosis

My project aims to discover genetic and genomic mechanisms that cause MND, and I have made good progress during the first 18 months of my PhD. Using custom computer code, I have looked at the full genetic sequences (genomes) of three identical twin sets where one twin has MND while the other is unaffected, to look for DNA code changes that might cause disease. However, I found that all three sets are completely genetically identical, meaning that other molecular differences must exist between the affected and unaffected twins that cause MND. Next, we will examine whether any gene products are expressed differently between the affected and unaffected twin to see if this could cause MND. I have also examined DNA sequences from four families with a history of ALS, to look for unique genetic alterations that may cause MND, and from thousands of genetic variant sites, I have narrowed the search to just 15-64 alterations that could possibly cause disease in each family. 

Victoria McLeod
Florey Institute of Neuroscience and Mental Health, University of Melbourne

Androgen Receptor Dysregulation in ALS

Androgen receptor (AR) is found to be expressed in muscle cells and motor neurons where its activation by androgens has been linked to growth and survival of motor neurons, and its impairment leads to Kennedy’s Disease. On this premise, we hope to identify and confirm some of the key gene targets regulated by AR in these cells and how altered AR signaling in ALS may contribute to motor neuron vulnerability. Flutamide, a drug which blocks the action of AR, when given to SOD1G93A mice, altered early disease progression and promoted muscle pathology with survival comparable to mice given a placebo. Studies are now underway to both genetically delete AR from motor neurons and elevate expression in SOD1G93A mice which will provide a more robust approach to delineate the role of AR in ALS disease progression.


Travel grants

Jenny & Graham Lang Collaboration Travel grant

Dr Frederik J Steyn
Univeristy of Queensland Centre for Clinical Research

Re-evaluation of hypermetabolism and the assessment of endogenous adipose as a modifier of ALS/MND progression

I travelled to the Utrecht Medical Centre to update Professor Leonard van den Berg and his group on research progress for our multi-centre study into energy needs in people living with MND. I also updated his group on the methods that we are using, so that we can streamline data collection and analysis across Australia and the Netherlands. My visit to Utrecht also allowed us to expand our collaboration to include studies on the role of gut bacteria in MND. 

Following this, I visited the laboratory of Professor Pierre-Francois Pradat at the Pité-Salpêtrière Hospital in Paris. We formulated a collaborative strategy to amalgamate our research. As part of these discussions, we formed a new research alliance with Dr Gaelle Bruneteau. Working with Dr Bruneteau and Professor Pierre-Francois, we will conduct complementary studies to define the impact of lower motor neuron loss on metabolism in MND. We are now preparing grant strategies for European-based research funding to support this new collaboration.

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