Mitochondrial matters of the brain: the role in Huntington's disease.
Even before the discovery of the mutant htt gene as the cause of Huntington's Disease (HD), abnormal energy metabolism and mitochondrial dysfunction had been suggested as a possible pathogenic mechanism in HD. These initial investigations described defects in energy metabolism using Positron Emission Tomography (PET) and Nuclear Magnetic Resonance (NMR) Spectroscopy in symptomatic and pre-symptomatic HD patients. Concurrently, 3-nitroproprionic acid, a mitochondrial complex II inhibitor, was found to replicate many of the pathological and clinical features of HD when administered to animals. Subsequently, reductions in mitochondrial respiratory chain enzyme activities in HD brain and muscle, HD mice models and cellular HD models were discovered and confirmed impaired mitochondrial function as an important component of pathogenesis. A unifying hypothesis linking chronic ATP depletion, oxidative stress and mitochondrial dysfunction culminated in the "slow excitotoxic theory" of HD pathogenesis. More recently, the localization of mutant htt within mitochondria and the association between transcriptional dysregulation caused by impaired PGC-1 alpha activity with abnormal mitochondrial biogenesis and function has provided further links with additional potential pathogenic mechanisms.
Turner
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MRC Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
Schapira
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AH
D000818:Animals; D001921:Brain / Q000473:pathology*; D004734:Energy Metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D006816:Huntington Disease / Q000209:etiology* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors
D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors