Oxidative stress has been hypothesized to be a major factor in the etiology of many progressive age related neurodegenerative diseases including Alzheimer and Parkinson disease, amytrophic lateral sclerosis, Friedreichs ataxia, and the prion diseases. The chief source of oxidative stress within the cell is the mitochondrion. The main ROS produced is the superoxide radical ( O'~) which under normal circumstances is reduced to H2O2 via the mitochondrial form of superoxide dismutase (Sod2). We have previously reported that inactivation of this gene results in neonatal lethality accompanied by a dilated cardiomyopathy, hepatic lipid accumulation, oxidative DNA damage, organic aciduria, spongiform encephalopathy, gliosis, and mitochondrial enyzmatic abnormalities. We have also demonstrated that many of these phenotypes can be ameliorated by synthetic antioxidant treatment. The long term goals of these studies are to 1) understand the molecular targets of mitochondrial oxidative stress both at the genetic and protein level within the brain, & 2) characterize the efficacy of synthetic antioxidants in preventing many of the CNS disorders which present due to mitochondrial oxidative stress within the brain.
The specific aims are 1) Characterize the metabolism of the affected areas of the brain to determine if there is a metabolic differential relative to unaffected areas; 2) Determine whether cell loss contributes to the progression of the spongiform changes; 3) Characterize at the biochemical and enzymatic level the changes due to mitochondrial oxidative stress within the brain and the efficacy of various synthetic antioxidants in attenuating such changes; 4) Investigate gene expression changes in the brain in relation to endogenous mitochondrial oxidative stress via microarray analysis. Experimental methods include; growth and harvesting of Sod2 mutant mice and controls with and without synthetic antioxidant treatment, histopathological analysis, stereological cell counting, metabolic measurements via 2-deoxyglucose labeling, biochemical analysis of mitochondria from control and experimental groups, and microarray analysis of RNA from control and experimental groups of both affected and unaffected areas.
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