The Physiological Functions of Synucleins

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disease affecting millions of people. Synaptic dysfunction is an early event in the pathogenesis of the disease occurring prior to the onset of symptoms. Therapeutic interventions at these early stages hold the promise of slowing or even halting the disease. The biggest obstacle to the development of such therapies is a lack of knowledge of early molecular and synaptic events that occur in PD. Therefore, our long term objective is to understand the mechanisms of synaptic dysfunction in PD. a-Synuclein was the first gene identified to cause dominant familial PD, and is also the major constituent of Lewy bodies, the pathological hallmarks of PD. Hence, considerable effort is being directed at understanding the role of a-synuclein in the pathogenesis of PD. However, these efforts are focused mostly on toxic gain-of- function approaches, such as its aggregation. In contrast, little is known about the normal physiological functions of a-synuclein at the presynaptic terminal and its contribution to PD. This is the objective of our proposal. We have generated a novel mouse that lacks all synucleins to facilitate these studies. To attain the objective of this application, three aims are pursued. First, the interaction of synucleins with newly identified physiological partners and the bilayer will be examined. Second, the synaptic transmission deficits of synuclein null neurons will be characterized in culture and in vivo. Third, we will study how PD mutations impact these physiological properties and functions. Achieving these goals is important for human health, given aging demographics and the increasing prevalence of neurodegenerative diseases.