Long-term goal. The long-term goal of the proposed study is to understand the role of mitochondria and oxidative stress in the dopaminergic cell death, associated with the Parkinson's disease. Hypothesis. The hypothesis to be tested is that (a) an increase in the steady-state levels of nitric oxide stimulates both dopamine autoxidation and mitochondrial oxidant production; (b) the ensuing increase in the oxidative load of the dopaminergic cell leads to specific mitochondrial dysfunctions.
Specific Aims. The testing of the biochemical pathway envisioned by this hypothesis will constitute the specific aims of this study, which include: (1) Determine how nitric oxide regulates autoxidation of dopamine, a process which generates reactive oxygen species and nitrogen-centered oxidants. (2) Determine the effects of nitric oxide and dopamine on mitochondrial functional integrity in intact cells. (3) Identify the mitochondrial proteins that become oxidized by reactive species derived from dopamine autoxidation. (4) Explore the mechanisms by which oxidative/nitrosative damage to mitochondria may be attenuated. Collectively, these studies will attempt to scrutinize the plausibility of a biochemical model explaining the deleterious alterations occurring during Parkinson's disease. Significance. Specifically, the results in this study will help elucidate the mechanisms by which nitric oxide induces autoxidation of dopamine and leads to the impairment of mitochondrial functions. Understanding of the nature of the putative mechanisms is deemed to be an indispensable step in developing therapeutic interventions.
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