title: Mitochondria and Huntington's disease pathogenesis: insight from genetic and chemical models.
abstract: A mechanistic link between cellular energetic defects and the pathogenesis of Huntington's disease (HD) has long been hypothesized based on the cardinal observations of progressive weight loss in patients and metabolic defects in brain and muscle. Identification of respiratory chain deficits in HD postmortem brain led to the use of mitochondrial complex II inhibitors to generate acute toxicity models that replicate aspects of HD striatal pathology in vivo. Subsequently, the generation of progressive genetic animal models has enabled characterization of numerous cellular and systematic changes over disease etiology, including mitochondrial modifications that impact cerebral metabolism, calcium handling, oxidative damage, and apoptotic cascades. This review focuses on how HD animal models have influenced our understanding of mechanisms underlying HD pathogenesis, concentrating on insight gained into the roles of mitochondria in disease etiology. One outstanding question concerns the hierarchy of mitochondrial alterations in the cascade of events following mutant huntingtin (mhtt)-induced toxicity. One hypothesis is that a direct interaction of mhtt with mitochondria may trigger the neuronal damage and degeneration that occurs in HD. While there is evidence that mhtt associates with mitochondria, deleterious consequences of this interaction have not yet been established. Contrary evidence suggests that a primary nuclear action of mhtt may detrimentally influence mitochondrial function via effects on gene transcription. Irrespective of whether the principal toxic action of mhtt directly or secondarily impacts mitochondria, the repercussions of sufficient mitochondrial dysfunction are catastrophic to cells and may arguably underlie many of the other disruptions in cellular processes that evolve during HD pathogenesis.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA. Susan_Browne@Merck.com
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D008957:Models, Genetic; D009154:Mutation