Parkinson's disease is the most common aging-related movement disorder affecting more than 1.8% of individuals over age 65. A small protein, alpha-synuclein, might be central to the pathogenesis of both rare familial and common sporadic forms of the disease. Drosophila transgenic for human alpha-synuclein faithfully replicate essential features of the human disease including age-dependent, progressive degeneration of dopaminergic neurons, Lewy-body-like inclusion formation and movement disorder. This Drosophila model of Parkinson's disease is ideally suited for genome-wide expression analysis during aging and powerful genetic manipulation of molecular mechanisms leading to dopaminergic cell death. We hypothesize that microarray analysis of alpha-synuclein transgenic Drosophila will identify genes controlling neurodegeneration. We will define genes differentially transcribed in alpha-synuclein transgenic Drosophila during aging and genetically validate a novel suppressor or enhancer of alpha-synuclein pathology. To that end we will pursue three Specific Aims: 1) We will determine genes differentially transcribed at progressive ages in the Drosophila model of Parkinson's disease. 2) We will genetically validate a top priority microarray derived candidate modifier. 3) We will characterize the mechanism modifying alpha-synuclein-induced neurodegeneration by detailed analysis of the implicated pathway. The combined genomic and genetic analysis of Parkinson's disease in aging alpha-synuclein transgenic Drosophila will identify a fundamental pathogenic mechanism and elucidate novel therapeutic targets for the human disease. The mammalian homolog of the Drosophila modifier will be a candidate susceptibility gene for human Parkinson's disease. These studies will expand the Candidate's expertise in bioinformatics and provide exceptional training in Drosophila genetics in the superb research environment of Harvard Medical School and Brigham and Women's Hospital.