title: Oxidative damage in Huntington's disease pathogenesis.
abstract: Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the progressive development of involuntary choreiform movements, cognitive impairment, neuropsychiatric symptoms, and premature death. These phenotypes reflect neuronal dysfunction and ultimately death in selected brain regions, the striatum and cerebral cortex being principal targets. The genetic mutation responsible for the HD phenotype is known, and its protein product, mutant huntingtin (mhtt), identified. HD is one of several "triplet repeat" diseases, in which abnormal expansions in trinucleotide repeat domains lead to elongated polyglutamine stretches in the affected gene's protein product. Mutant htt-mediated toxicity in the brain disrupts a number of vital cellular processes in the course of disease progression, including energy metabolism, gene transcription, clathrin-dependent endocytosis, intraneuronal trafficking, and postsynaptic signaling, but the crucial initiation mechanism induced by mhtt is still unclear. A large body of evidence, however, supports an early and critical involvement of defects in mitochondrial function and CNS energy metabolism in the disease trigger. Thus, downstream death-effector mechanisms, including excitotoxicity, apoptosis, and oxidative damage, have been implicated in the mechanism of selective neuronal damage in HD. Here we review the current evidence supporting a role for oxidative damage in the etiology of neuronal damage and degeneration in HD.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA. Susan_Browne@Merck.com
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype