Oxidative stress has been proposed as a critical mechanism underlying metabolic dysfunction in diseases and aging and has been implicated in both apoptotic and necrotic cell death. Oxygen-derived free radicals are a normal byproduct of respiration and oxidative metabolism. Normally cells have efficient protective mechanisms which can quench radicals. When there is a compromise in cellular antioxidants or an increase in production of free radical species, neuronal damage occurs. An increasing body of evidence has implicated oxidative damage in the pathogenesis of Parkinson's disease (PD), including evidence of increased lipid peroxidation, protein oxidation, and oxidative damage to both nuclear and mitochondrial DNA directly associated with the known topographic and neuronal distribution of pathology observed within PD. The investigators preliminary studies may provide the strongest evidence yet, and they hypothesize that a connection exists between the pathology observed in PD and oxidative damage leading to metabolic dysfunction in this disorder. Their first Specific Aim is to determine the topographic distribution of markers for oxidative damage to protein, lipid, and DNA fractions in postmortem PD brains, using antibodies to several epitopes associated with oxidative damage. They will provide a direct assessment of markers for oxidative damage to determine if they are altered and subsequently correlate them with the selective neuronal vulnerability and the neuro-pathologic hallmarks associated with PD. Their goal will be to develop biochemical markers which may be useful for diagnostic purposes, monitoring disease progression, and the effectiveness of therapeutic interventions. The second Specific Aim will utilize transgenic animal models and therapeutic interventions to assess the role of oxidative stress in MPTP neurotoxicity. The systemic administration of the toxin MPTP in experimental animals replicates the neuropathological, neurochemical, and clinical features in PD, causing cell death by inducing oxidative stress. They will examine whether transgenic mice with a knockout of the manganese superoxide dismutase gene and neuronal nitric oxide synthase gene, as well as those overexpressing bcl-2 show increased vulnerability or resistance, respectively, to MPTP neurotoxicity. They will investigate the use of novel therapeutic strategies, using free radical spin traps, neuronal nitric oxide synthase inhibitors, and dietary creatine supplementation to block MPTP neurotoxicity. These studies will have direct relevance to understanding the pathogenesis of PD and to developing new therapies.
