Alpha-synuclein was first implicated in familial Parkinson's disease but is also a major component of the Lewy body pathology, found in sporadic disease. Over-expression of the gene in fruit flies is sufficient to recapitulate aspects of Parkinson's disease, including the selective loss of dopaminergic neurons, Lewy-like inclusions and a specific movement disorder that responds favorably to L-DOPA treatment (Feany and Bender, 2000). We hypothesized a similar mechanism may contribute to risk in human disease. By looking at specific variants spanning the gene we found evidence for association in patients with Parkinson's disease (see Farrer et al., 2001). This has been replicated in a separate population and appears to be conferred by the alpha-synuclein promoter. Our Fox proposal is to further characterize variability within the gene, to determine the haplotype diversity present and identify a simple genetic assay (haplotype-tagging SNPs) associated with disease risk. We will extend our analysis to Parkinson's disease in other populations and to pathologically confirmed Lewy body disease. The ratio of alpha-synuclein expression (of discrete mRNA alleles) will be examined in post-mortem brain tissue of individuals in which specific genetic variability has been implicated in disease. Our work intends to provide a simple biomarker for Parkinson's disease, and more generally synucleinopathies, which may facilitate diagnosis and better treatment.