Many forms of neurodegeneration are associated with oxidative stress. Although the molecular mechanisms of neurodegeneration remain unknown, it has been proposed that the symptoms associated with several late-onset neurodegenerative diseases are the result of mitochondrial dysfunction and increased production of mitochondrial- generated reactive oxygen species (ROS). Preliminary studies using quantitative polymerase chain reaction show an age-associated increase in basal levels of mouse brain mitochondrial DNA (mrDNA) damage. We hypothesize that oxidative damage to mtDNA leads to a decline in mitochondrial function with concomitant increase in mitochondrial- generated ROS. The hypothesis predicts that impairment of mitochondrial function due to oxidative mtDNA damage can lead to neuronal apoptosis. Increasing evidence implicates apoptosis as a major mechanism of cell death in neurodegeneration is yet not known. This project will explore the molecular mechanisms of neuronal cell death by using the 3-nitropropionic acid (3-NPA) animal model of Huntington's disease. Recent evidence has suggested that 3-NPA, a mitochondrial neurotoxin, can lead to striatal apoptosis and neurodegeneration. is caused by an accumulation of mtDNA damage induced by oxidative stress. To test this hypothesis this application proposes: 1) to examine the association between mtDNA damage and apoptosis in mouse brain exposed to 3-NPA; 3) to examine the association between mitochondrial dysfunction and oxidative stress exposed to 3-NPA; 3) to determine the association between mtDNA damage, ROS production, and apoptosis in mouse striatum exposed to 3-NPA; and 4) to analyze the effect of inhibitors of caspases in mouse striatum on mtDNA damage, generation of mitochondrial ROS, and apoptosis after treatment with 3-NPA. This study will lead to a better understanding of the role of oxidative stress and mitochondria in apoptosis associated with neurodegeneration.
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