Parkinson's disease is a severe neurodegenerative disorder affecting millions of people annually. Alpha, beta and gamma synucleins constitute a family of abundant presynaptic proteins that probably function in regulating neurotransmitter release. Interestingly, alpha synuclein forms pathological aggregates in Parkinson's disease, and mutations in alpha synuclein are associated with Parkinson's disease in humans. This suggests a role for alpha synuclein in the pathogenesis of Parkinson's disease. The overall goal of the current application is to achieve such an insight.
It aims to elucidate the physiological functions of synucleins to determine the structural properties that underlie these functions, and to unravel the mechanisms that mediate the role of synucleins in Parkinson's and other neurodegenerative diseases.
Five specific aims are proposed to pursue this goal. First we describe experiments to study the relative expression and localization of synucleins. In the second specific aim we suggest studies to examine the biological properties, binding to phospholipids and other targets, and phosphorylation of wild type and mutant synucleins. Synucleins are natively unfolded but fold upon binding to a target. Therefore we propose to study in the third specifc aim the three dimensional structure of synucleins after binding to a target using circular dichroism and nuclear magnetic resonance spectroscopy. The fourth specific aim will examine the essential functions of synucleins in knock out mice. In the fifth specific aim we propose to analyse the effect of overexpressing wild type and mutant synucleins in transgenic mice. These transgenic experiments will complement the knock out approach to testing function, and will determine if a transgenic model of Parkinson's disease can be generated. We anticipate that these experiments will establish a molecular understanding of synuclein functions in the brain and provide insight into the role of an alpha synuclein in Parkinson's disease.
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