There is a large body of evidence that both defective energy metabolism as well as oxidative damage, which is a consequence of increased production of free radicals, may play a critical role in Parkinson's disease pathogenesis. Prior studies have shown that markers of oxidative damage to lipids, proteins and DNA are increased in the substantia nigra of Parkinson's disease patients. We intend to investigate the role of a novel antioxidant enzyme system, methionine sulfoxide reductase A. This enzyme may play a critical role in prevention of aging related oxidative damage and loss of dopamine. We will determine whether overexpression of this enzyme can protect cultured cells against damage produced by several mitochondrial toxins. We will also determine whether overexpression of this enzyme in fruit flies prevents age-dependent reductions in dopamine and lastly we will determine whether overexpression of this enzyme in mice protects them against the parkinson-related neurotoxin MPTP. This toxin produces a parkinsonian syndrome in mice, primates and humans. If these studies are successful, they will identify an important new target, which may be utilized to develop novel therapies for the treatment of Parkinson's disease.