Oxidative stress in Huntington's disease.
It has been five years since the elucidation of the genetic mutation underlying the pathogenesis of Huntington's disease (HD) (97), however the precise mechanism of the selective neuronal death it propagates still remains an enigma. Several different etiological processes may play roles, and strong evidence from studies in both humans and animal models suggests the involvement of energy metabolism dysfunction, excitotoxic processes, and oxidative stress. Importantly, the recent development of transgenic mouse models of HD led to the identification of neuronal intranuclear inclusion bodies in affected brain regions in both mouse models and in HD brain, consisting of protein aggregates containing fragments of mutant huntingtin protein. These observations opened new avenues of investigation into possible huntingtin protein interactions and their putative pathogenetic sequelae. Amongst these studies, findings of elevated levels of oxidative damage products such as malondialdehyde, 8-hydroxydeoxyguanosine, 3-nitrotyrosine and heme oxygenase in areas of degeneration in HD brain, and of increased free radical production in animal models, indicate the involvement of oxidative stress either as a causative event, or as a secondary constituent of the cell death cascade in the disease. Here we review the evidence for oxidative damage and potential mechanisms of neuronal death in HD.
Browne
S E
SE
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA. browne@helix.mgh.harvard.edu
Ferrante
R J
RJ
Beal
M F
MF
D000818:Animals; D016923:Cell Death / Q000502:physiology; D003342:Corpus Striatum / Q000473:pathology; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D018911:Trinucleotide Repeats / Q000235:genetics