The number of people with Parkinson's disease (PD) is increasing rapidly because life expectancy of people in developed countries continues to rise. Without a medical breakthrough the number of people afflicted with PD will continue to rise, threatening to make this condition an unmanageable burden not only for the patients but also for society in general. Although significant progress has been made, to date this disorder is neither curable nor preventable. For this project, we propose a new concept of PD pathogenesis that promises a novel therapeutic approach focusing on the role of negative modulators of protein aggregation. Recent studies have shown that abnormal accumulation of alpha-synuclein is centrally involved in the pathogenesis of PD. Thus, identification of factors promoting and inhibiting alpha-synuclein aggregation is of critical importance for understanding the pathogenesis of PD and developing new treatments. Our preliminary studies suggest that b-synuclein, the non-amyloidogenic homologue of alpha-synuclein, inhibits alpha-synuclein aggregation. We postulate that b-synuclein is a naturally occurring anti-aggregation molecule that might prevent the neurotoxic effects of alpha-synuclein making it a suitable target for the development of an alternative gene therapy for PD and other disorders with Lewy bodies (LBs). In this context, we plan to determine if b-synuclein blocks alpha-synuclein aggregation and neurodegeneration in a transgenic (tg) model of PD. Our hypothesis is that b-synuclein might play an important role in regulating alpha-synuclein aggregation in vivo. To test this hypothesis, alpha-synuclein tg mice will be crossed with b-synuclein tg animals. The animals will undergo detailed behavioral, neurochemical and neuropathological analysis. We also plan to assess the potential anti-parkinsonian effects of a recombinant adeno-associated viral vector (rAAV) expressing b-synuclein in the alpha-synuclein tg model. For this purpose, alpha-synuclein tg animals will be treated with rAAV expressing b-synuclein. The animals will undergo detailed behavioral, neurochemical and neuropathological analysis to determine whether expression of b-synuclein affects the functional and structural alterations promoted by alpha-synuclein and might act as a basis for gene therapy for PD and other disorders with LBs. Taken together, these studies will help to better understand the role of alpha-synuclein and b-synuclein on PD and to develop a novel treatment approach to the disease.