Parkinson's disease is a devastating disease that robs its victims of the ability to direct and control normal movement. These symptoms result from the death of a particular class of nerve cell in the brain that secretes a chemical messenger called dopamine. A variety of studies have incriminated the protein alpha-synuclein as a primary culprit in this disease, but the reasons for alpha-synuclein's toxicity remain elusive. To understand more precisely how alpha-synuclein affects nerve cells, studies were recently carried out with a single-celled organism that nevertheless shares many basic features of a human cell, the common baker's yeast. A modified version of baker's yeast was created that produces human alpha-synuclein protein, and this yeast strain was then used in genetic experiments to identify yeast genes that influence the toxicity of alpha-synuclein. Many of the genes identified in yeast have counterparts in higher organisms, including humans. The goal of the current proposal is to determine whether these genes affect alpha-synuclein toxicity in the context of a functioning brain. We have chosen to address this question in the fruit fly, Drosophila melanogaster, one of the simplest organisms that have dopamine-secreting nerve cells. We have genetically modified fruit flies to produce human alpha-synuclein protein in dopamine-secreting nerve cells and will test whether Drosophila genes similar to those identified in yeast influence the toxicity of alpha-synuclein in these cells. This work may ultimately explain how alpha-synuclein acts to kill dopamine neurons in humans. An understanding of the mechanisms by which alpha-synuclein kills dopamine neurons may make it possible to develop therapeutic strategies to treat and possibly cure Parkinson's disease.