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Role of the male-specific gene SRY in Parkinson's disease
Summary
We are testing the novel concept that the male sex-determination gene SRY is a factor involved in the susceptibility of males to Parkinson’s disease. We will address this by determining whether SRY levels are altered in Parkinson’s disease and whether inhibition of SRY function can reduce the progression of Parkinson’s disease using animal models.
Description
Parkinson's disease (PD) is a neurological disorder that causes slowness in movement, tremors, and postural disturbances. Interestingly, PD occurs 1.5 times more often in men than in women. We think this could be due in part to the sex chromosome differences between males (XY) and females (XX).
We have evidence that SRY, the "male only" gene on the Y chromosome responsible for the presence of testicles, also makes SRY protein in men's brains. When SRY is removed from rats' brains, the male rats develop movement deficits reminiscent of those seen in PD, which are reversed when SRY levels are restored. The movement problems in PD and in these rats occur due to a reduction of an enzyme called tyrosine hydroxylase (TH) which is essential for dopamine production.
We have discovered that SRY can regulate TH in human dopamine-producing cells. Our current research aims to address the role of SRY in Parkinson's disease, which is caused by the loss of dopamine producing cells in the substantia nigra.
We are interested in whether SRY is involved in the male susceptibility to Parkinson's disease. We aim to test this by generating animal models of Parkinson's disease and assess whether altering SRY function can slow or reduce the dopamine cell death and motor impairment in this model.
The proposed projects will provide entirely novel and important insights into the molecular and cellular mechanisms of gender differences in Parkinson's Disease. Ultimately, this work may help to explain the differential vulnerability of males and females to disorders characterized by dopaminergic dysfunction.
Funding
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National Institutes of Health (US)
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Rebecca L. Cooper Medical Research Foundation
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Helen McPherson Smith Trust
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Contributing to Australian Scholarship and Science (CASS) Foundation
Outcomes
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Established rat model of Parkinson's disease
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Established rodent stereotaxic surgery, including site-specific injections and cannulation of brain structures
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Established behavioural assays for Parkinson's disease
Selected Publications
Lee, J. and Harley, V. Sex differences in catecholamine regulation. Bioessays. Accepted 24/1/12
Lee, J., Zhu, W.M., Stanic, D., Finkelstein, D.I., Horne, M.H., Henderson, J., Lawrence, A.J., O'Connor, L., Tomas, D., Drago, J., and Horne, M.K. Sprouting of Dopamine Terminals and Altered Dopamine Release and Uptake in Parkinsonian Dyskinesia. Brain. 131 (pt6), 1574-87 (2008).
Lee, J., Gomez-Ramirez, J., Johnston, T., Visanji, N., Brotchie, J.M. Receptor-activity modifying protein 1 (RAMP1) expression is increased in the striatum following repeated L-DOPA administration in a 6-hydroxydopamine lesioned rat model of Parkinson's disease. Synapse. 62(4), 310-313 (2008).
Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 16(4):415-20 (2006).
Lee, J., Di Marzo, V., and Brotchie, J.M. Role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats. Neuropharmacology. 51, 557-565 (2006).
Brotchie, J.M., Lee, J., and Venderova, K. L-DOPA-induced dyskinesia in Parkinson's disease. Journal of Neural Transmission,112(3), 359-91. (2005).