Bill Gole Postdoctoral Fellowships for MND Research   The research fellowships of the MND Research Institute of Australia aim to encourage young researchers to focus their interest on MND. The Institute is pleased to announce the award of a new postdoctoral Fellowships for 2010-2012 in memory of the late Bill Gole to:   Dr Shu Yang Institution:  ANZAC Research Institute, Concord, NSW Project:  Investigating the role of recently identified mutant genes in MND pathogenesis. Summary:  The cause of the MND is unknown. Our research aims to identify the cause of MND at the gene level. We previously found mutations in genes (TDP-43 and FUS) that cause MND in several familial and sporadic cases. These genes appear to play key roles in MND pathogenesis. We will investigate the biological functions of these genes and the effects of the mutations. This research will help us to gain a better understanding of the disease mechanism and aid the development of MND therapies. The disease mechanism underlying motor neuron disease (MND) is currently poorly understood, making the development of diagnostic tools and therapeutics difficult. However, proteins that play fundamental roles in MND pathogenesis have recently been identified, providing new hope for understanding the cause of MND and development of therapeutic and diagnostic tools. The 43 kDa TAR DNA binding protein (TDP-43) was recently identified as a signature component of the abnormal protein aggregates found in the brain and spinal cord of most sporadic and familial MND patients. Our group identified several mutant forms of TDP-43 that appear to directly trigger neurodegeneration leading to MND (funded by a Bill Gole Fellowship to Dr Blair, 2006-2007). We hypothesise that identifying the mechanisms through which rare TDP-43 mutations cause MND will be more widely relevant to understanding the cause of familial and sporadic MND. We will establish novel TDP-43-expressing MND cell models and a transgenic mouse model to study the function of mutant TDP-43 protein. The significance of the proposed project includes a greater understanding of how mutant TDP-43 leads to protein aggregation and motor neuron degeneration in MND, as well as knowledge of the functions of other signature proteins in MND, such as FUS, that may provide new diagnostic and therapeutic targets. The establishment of the TDP-43 transgenic mouse model may provide a better model to understand sporadic MND pathogenesis than the existing SOD1 transgenic mouse models. This model may also act as a useful platform for MND therapeutic development.    Other Bill Gole MND Research Fellows   Dr Justin Yerbury (2009 - 2011) Institution:  Centre for Medical Biosciences, University of Wollongong Project:  Probing molecular mechanisms of microglial and astrocyte activation in ALS. Summary:  This project combines unique expertise to perform truly pioneering studies to determine how a genetic defect in a protein, superoxide dismutase, affects immune processes implicated in motor neuron disease. Novel approaches will be used to study relevant molecular interactions, both in the test tube and in animal models. The outcomes will provide a new understanding of these processes and may contribute towards the ultimate development of new therapies.  Recent research suggests that a soluble factor in ALS CSF is toxic to motor neurones via both direct and indirect effects; the latter is thought to involve activation of microglial cells which secrete toxic mediators.  One potential soluble factor that may promote cell activation and neurotoxicity is extracellular mSOD1.  This project will provide significant insights into the mechanisms by which extracellular mSOD1 influences the development of familial ALS (fALS) pathology.  We expect that the research outcomes will stimulate a high level of general interest resulting in publications in high impact international scientific journals and provide vital clues to possible new directions for therapies to combat fALS, for which there is currently no effective treatment.   Dr Anna King (2008 - 2010) Institution:  NeuroRepair Group, Menzies Research Institute, University of Tasmania Project:  Investigating the causes and consequence of axonal pathology in amyotrophic lateral sclerosis. Summary:  Motor neurone disease (MND) is caused by a loss of function of the nerve cells controlling the muscles.  I have recently developed a cell culture model which mimics the degenerative changes in motor nerve cells that underlie the onset of amyotrophic lateral sclerosis, the major cause of human MND.  I will use this model to investigate the factors and mechanisms that cause motor neurons to degenerate, an approach which may indicate new therapeutic opportunities for an otherwise incurable condition.   Dr Jennica Winhammar (2008 - 2010) Institution:  Dept of Neurology, The Prince of Wales Medical Research Institute, NSW Project:  Clinical trial to assess the neuroprotective properties of a sodium channel blocking agent in motor neurone disease Summary: This project will provide clinical trial information related to the potential neuroprotective properties of a sodium channel blocking agent in patients with motor neurone disease. Specifically, it will establish whether the sodium channel blocking agent can slow disease progression.  A potential therapeutic response would provide impetus for a larger scale, multi-centre clinical trial. In addition to providing information about potential mechanisms of neurodegeneration and their treatment, new quantifiable measures will be further developed to objectively monitor MND patients in a clinical trials setting.   Dr Julia Morahan (2007 - 2008) Institution: The University of Sydney Project: Somatic mutations in sporadic motor neuron disease? Summary:  The cause of sporadic ALS is not known but genetic abnormalities have long been suspected.  Some gene mutations are only seen in certain tissues of the body and are not passed on to the next generation.  I expect to find these mutations in the brain, but not blood or sperm cells, of people with sporadic ALS.  Finding mutations in these genes would lead to an understanding of the cause of sporadic ALS and lead to more effective therapy.   Dr Ian Blair  (2006 - 2007) Institution: ANZAC Research Institute, Concord NSW Project: Identification of novel genes involved in motor neurone degeneration Summary: We aim to identify new mutated genes responsible for disorders affecting motor neurones using genetic linkage studies in families with hereditary motor neuropathies (HMN).  HMNs are slowly progressive, non-fatal disorders of motor neurones.  Discovery of gene mutations in these families will tell us about the pathways leading to the death of motor neurones.  This should ultimately lead to more effective diagnosis and the development of drugs to prevent and treat both familial and sporadic forms of MND.   Valerie Hansen (2005 - 2006) Institution: University of Sydney Project: Susceptibility to enteroviral infection: a cause of MND? Summary: Many people suspect that sporadic Motor Neuron Disease (SMND) is caused by a virus that specifically targets motor neurons. With this Research Fellowship Valerie plans to undertake a project that shows that people with SMND are genetically susceptible to a group of viruses that allows these viruses to attack motor neurons.   Dr Roger Chung (2005) Institution: University of Tasmania Project: Excitotoxicity and cytoskeletal alterations in the pathogenesis of Motor Neurone Disease Summary: Glutamate is the key chemical neurotransmitter involved in the cellular signalling between nerve cells within the brain. However, changes in this system, caused by either injury of disease, lead to abnormal cellular functions and ultimately neuron death. The underlying feature of this is sustained exposure to glutamate, leading to neuronal death, termed excitotoxicity. Excitotoxicity has been implicated in the development of MND, but it is not clear if over-activation of glutamate receptors leads to the specific patterns of nerve cell changes characteristic of MND, and in particular the changes involving neuronal cytoskeletal proteins. Furthermore, it is not entirely clear why motor neurones are particularly susceptible to excitotoxicity. This Project will determine whether excitotoxicity can directly or indirectly cause changes in cytoskeletal proteins that are characteristic of MND, and whether the specific cytoskeletal composition of motor neurones contributes to their selective vulnerability. Finally, Dr Chung will explore whether a recombinant protein which promotes brain healing (that his team has developed) may also have a neuroprotective role in MND.