Parkinson's disease is the most common debilitating movement disorder of the aging human population. The neurons that degenerate in Parkinson's disease are subject to increased oxidative stress because superoxide and other reactive species are generated during dopamine metabolism. 6-hydroxydopamine (6-OHDA) is a redox cycling dopamine analog, which can be targeted to selectively damage the nigrostriatal system that degenerates in Parkinson's disease. Phosphotyrosine signaling pathways activated by neuroprotective factors, such as brain derived neurotrophic factor and glial cell line-derived neurotrophic factor, are important for dopaminergic neuron function and survival. This proposal is designed to investigate the hypothesis that oxidant-mediated alterations in phosphotyrosine signaling contribute to degeneration of dopaminergic neurons in Parkinson's disease. Nitrotyrosine, a marker of oxidative stress involving peroxynitrite formation, is increased in both the 6-OHDA rodent model and in human Parkinsonian brain tissues. Peroxynitrite is formed from the reaction of superoxide with nitric oxide, implicating these free radicals in the pathogenesis of Parkinson's disease. In this proposal, mechanisms by which 6-OHDA, superoxide, and nitric oxide affect phosphotyrosine signaling cascades will be investigated using immortalized dopaminergic neuron lines and mice with genetically altered levels of extracellular superoxide dismutase. This comprehensive set of studies will yield important insights concerning mechanisms by which oxidative stress affects neurotrophic signaling in dopaminergic neurons, potentially contributing to development of combined antioxidant-neurotrophic factor therapies for Parkinson's disease.
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