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- Dr Robyn Wallace - Molecular mechanisms of motor neuron disease and epilepsy
Dr Robyn Wallace - Molecular mechanisms of motor neuron disease and epilepsy
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After completing her BSc(Hons) at Flinders University in 1994, Dr Wallace commenced a PhD under the supervision of renowned geneticists John Mulley and Grant Sutherland. During her PhD, Dr Wallace discovered the first gene for a form of idiopathic generalized epilepsy. Following the awarding of her PhD from the University of Adelaide in 1998, she worked with Bionomics Ltd to develop drug targets and genetic tests for epilepsy. In 2002, Dr Wallace was appointed Assistant Professor at the University of Tennessee Health Science Center, where she extended her genetics experience to include the analysis of mouse epilepsy models. In 2005 Dr Wallace joined the Queensland Brain Institute as the inaugural Ross Maclean Senior Research Fellow. Her research goal is to understand how genetic variation contributes to human disease.
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Our group is focused on elucidating molecular mechanisms of diseases of the central nervous system. We are focusing on two disorders that are associated with nerve cell degeneration, motor neuron disease and epilepsy.
Motor Neuron Disease (MND) is a rare, incurable disorder with late onset. Although most MND cases are not familial, a small percentage are due to genetic mutations in the superoxide dismutase (SOD1) and TAR DNA binding (TDP-43) genes. We are using these transgenic mice to understand the mechanisms and to test potential treatments.
Epilepsy is a common, complex disorder with a strong genetic component. We have successfully identified several human epilepsy genes and we are continuing to characterise the functional consequences of the mutations.
Motor neuron disease (MND) projects
Gene Discovery
Through the Australian Phenomics Facility we have access to hundreds of mice carrying thousands of random point mutations. We are screening these mice for loss of motor function to identify genes relevant to MND. Five potential new MND mouse models have been identified that require further characterisation.
Gene function
Genetic mutations associated with both familial and sporadic MND have recently been identified in TDP-43. TDP-43 is a DNA/RNA binding protein involved in gene regulation. The function of TDP-43 in the nervous system is currently unknown and its role in the pathogenesis of MND remains unclear. We aim to determine how abnormal TDP-43 leads to loss of motor neurons in MND patients. Specifically, we will identify genes that are regulated by TDP-43 and determine whether these genes are altered in MND patients with TDP-43 mutations. These studies will improve our understanding of what causes MND and provide rational targets for new therapies.
Biomarker Discovery
Because the cause of MND is unknown, there is no definitive diagnostic test for MND. In addition, there is no definitive way to measure the progression of disease. This is important for patients and also in clinical trials. To this end, we will attempt to identify biological markers from MND patient blood samples, using flow cytometry. Gene expression levels will also be examined in blood samples from MND patients to identify molecular markers associated with MND.
Magnetic resonance imaging (MRI) is being used to track disease progression in mice that contract MND. We have developed novel imaging techniques that we now aim to apply to MND patients.
These studies will identify markers that can be used to diagnose and track progression of MND. The studies also have the potential to provide information about what causes MND, highlighting potential targets for drug development.
Epilepsy projects
Gene discovery
Two families with myoclonic epilepsy have been mapped to specific chromosomal regions. We are now screening candidate genes from these regions to identify the underlying disease-causing mutations.
Gene function
PRICKLE1 mutations are associated with a progressive myoclonic epilepsy and ataxia syndrome. We are examining the functional consequences of different PRICKLE1 mutations in vitro using cell culture and in vivo using a mouse model of epilepsy.
Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, Miyata S, Chen S, Gonzalez-Alegre P, Griesbach HL, Wu S, Nashelsky M, Vladar EK, Antic D, Ferguson PJ, Cirak S, Voit T, Scott MP, Axelrod JD, Gurnett C, Daoud AS, Kivity S, Neufeld MY, Mazarib A, Straussberg R, Walid S, Korczyn AD, Slusarski DC, Berkovic SF, El-Shanti HI. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.American Journal of Human Genetics. 83:1-10 (2008).
Freeman JL, Shouri MR, Izzillo PA, Rosenfeld JV, Mulley JC, Harvey AS, Berkovic SF. Somatic mutations in GLI3 can cause sporadic hypothalamic hamartoma and gelastic seizures. Neurology 70:653-656 (2008).
Walker TJ, White A, Black DM, Wallace RH, Sah P, Bartlett PF. Latent stem and progenitor cells in the hippocampus are activated by neural excitation. J Neurosci.28:5240-7 (2008).
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