Parkinson's disease (PD), the second most common neurodegenerative disorder, results from selective loss of midbrain dopamine neurons. Both oxidative stress and intracellular aggregation of proteins, including the protein alpha-synuclein, are implicated in this degeneration. However, the source of oxidative stress, the mechanism of alpha-synuclein deposition, and the relationship between them are unknown. We will examine the role of the neurotransmitter dopamine in generating oxidative stress by manipulating its synthesis, degradation and vesicular transport and measuring production of reactive oxygen species. We will also investigate the effect of dopamine-mediated oxidative stress on alpha-synuclein deposition in model cell culture systems. We will then use this information to determine conditions that promote alpha-synuclein deposition in transgenic mice expressing wild type human alpha-synuclein or a mutant alpha-synuclein that causes an autosomal dominant form of PD. Thus we hope to identify factors that promote oxidative stress in dopamine neurons and to better understand the mechanisms and significance of alpha-synuclein deposition in PD. This work will be conducted under the sponsorship Dr. Robert Edwards in the Departments of Neurology and Physiology at UCSF. Through this work I will learn new techniques in molecular biology, biochemistry and imaging that I will continue to apply to PD. Dr. Edwards and I have developed a training program that includes laboratory research, coursework and didactics that will enable me over the next five years to become an independent investigator concentrating on the neurobiology of PD. In the long term I intend to spend 75% or more of my time dedicated to scientific investigation of PD, and to direct my clinical activities toward patients with PD and other movement disorders.