The long-term goal of this research is to find the cause or causes of typical, late-onset sporadic Parkinson's disease (PD). To date the search for genetically determined risk factors that could enhance susceptibility to putative parkinsonogenic environmental toxins has been restricted primarily to genes/proteins involved in the transport or detoxification of putative environmental toxins. In this grant we will test the novel hypothesis that variations in the gene region (known as the ____promoter___ region) that regulates a protein known as alpha-synuclein, which appears to intimately involved in Parkinson's disease, in combination with one or more specific environmental exposures, cause typical, Lewy body, PD in a substantial proportion of those affected by the disorder. This application is novel in it is the first to test a hypothesis that directly links specific environmental exposures, with promoter region variability and alpha-synuclein expression. This research project builds on recent progress in developing a high-resolution map of alpha-synuclein promoter region, which was initiative originally supported by an MJFF Biomarkers award. We will take advantage of two unique research populations of individuals. The first is comprised of approximately 52,000 pesticide applicators in Iowa and North Carolina. The second is a rural working population in Central California located in an area where approximately 250 million pounds of pesticides applied annually. In both populations, blood for DNA is already being actively collected. In this study we will (i) assay genetic variability in the promoter region in DNA samples from both populations, (ii) assess whether risk for PD is enhanced in the presence of specific environmental exposures, and (iii) assess genetic and environmental effects jointly. Our findings are likely to identify causative relationships that would otherwise be overlooked if these variables were analyzed alone. Our goal is to clarify the complex relationship between genetic and environmental risk factors for PD. Ultimately, these studies could lead to strategies for early disease detection and primary prevention strategies.