Recent work evaluating gene defects leading to Parkinson's Disease (PD) suggests that accumulation of alpha-synuclein may be a critical step in the pathogenic mechanisms leading to Lewy body Parkinsonism. One of us (RM) has developed a rat model of alpha-synuclein over-expression which results in long term elevations of synuclein production and concomitant degeneration of tyrosine hydroxylase neurons in substantia nigra. Because the model uses intracranial gene-transfer with viral vectors, it has considerable versatility compared to transgenic models, where over-expression is constant throughout the lifespan. Vaccines, while traditionally viewed as prophylactic approaches to disease, are increasingly being viewed as therapeutic adjuncts in cancer and cardiovascular disease. Others of us (DM and KU) have found that immunization of transgenic mouse models of amyloid over-expression with the All peptide, is surprisingly effective in reducing the Alzheimer phenotype, both pathologically and behaviorally, that develops in this model of the disease. This application will use the new rat model of alpha-synuclein over expression to test the hypothesis that vaccination against alpha-synuclein could diminish the toxicity of this agent towards dopamine producing neurons. We will use immunization with whole recombinant protein and synthetic peptides and immunization with DNA vaccines. Initial studies will verify that these vaccination regimens can indeed produce high antibody titers in rats, and determine the active immunization regimen(s) that leads to high stable titers. We will next test the hypothesis that antibodies against synuclein produced by these vaccines can arrest the neurotoxicity of dopaminergic neurons caused by alpha-synuclein over expression. Additionally, we will examine direct injections of anti-synuclein antibodies into the brain, bypassing the blood-brain barrier, to evaluate the effectiveness of this approach in rescuing dopaminergic neurons. Success will encourage further development of a vaccine as a therapeutic agent in PD.