The hallmark lesions in the brains of patients with Parkinson's disease (termed Lewy bodies) are mainly composed of a-synuclein. This small protein normally regulates proper communication between nerve cells by modulating neurotransmitter release. However, a-synuclein has a propensity to form sticky fibers, a property that is enhanced by mutations found in a few families with hereditary Parkinson's disease. When introduced into mouse brain, the human a-synuclein gene causes the same pathology as in Parkinson's disease patients, ultimately leading to severe movement disorder and death of the experimental animals. In the present project, we will take advantage of our transgenic pre-clinical model of Parkinson's disease pathology to test experimental drugs. Given the strong evidence for oxidative damage in the affected brain regions of Parkinson's disease patients and animal models, we will emphasize on anti-oxidants and neuroprotective agents in the early preclinical trials. For example, melatonin, coenzyme Q10, and vitamin E are safe and easy to administer drugs with anti-oxidative efficacy. For novel, experimental drugs (spin traps and phenolic anti-oxidants), pharmacokinetics will be established in the pre-clinical model. When beneficial effects on the life span and locomotor behavior are observed for a given drug, the mechanism of action will be elucidated by histological and biochemical analysis of the transgenic mouse brains. Based on this preclinical study, we hope to gain important clues for the design of novel therapeutic approaches to treat Parkinson's disease.