Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder due to a mutation near the telomere of chromosome 4. Neuropathologic studies indicate a marked vulnerability of spinous Golgi II neurons in the caudate-putamen with onset of degeneration typically in mid- life. Notably, age of onset depends upon the sex of the transmitting parent. Intrastriatal injection of agonists for glutamate receptor subtypes, including NMDA, kainic acid (KA) or quisqualic acid (QA), caused a pattern of neuronal degeneration in the striatum resembling that of HD, prompting the hypothesis that endogenous glutamate causes the neuronal degeneration in HD via one of these receptors. Our research has focused on the postreceptor mechanisms responsible for QA/KA induced neuronal degeneration and has implicated oxidative stress as the proximate cause. These findings have led to trial of alpha-tocopherol and the centrally active antioxidant, idebenone, to prevent progression of HD in symptomatic individuals. In the proposed studies, we will define the pharmacologic mechanisms whereby idebenone and related drugs protect against KA striatal neurotoxicity in vivo. In addition, exploiting an in vitro model of Ca++- dependent delayed neurotoxicity due to KA, we shall determine the mechanisms of cytolysis, the role of oxidative stress, and effects of partially uncoupling mitochondrial oxidative metabolism. These studies may lead to insights into the proximate causes of HD neurodegeneration, thereby permitting pharmacologic preventive interventions.

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Johns Hopkins University
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