title: PGC-1α at the intersection of bioenergetics regulation and neuron function: from Huntington's disease to Parkinson's disease and beyond.
abstract: Neurons are specialized cells with unique features, including a constant high demand for energy. Mitochondria satisfy this constant demand, and are emerging as a central target for dysfunction in neurodegenerative disorders, such as Huntington's disease (HD) and Parkinson's disease. PPARγ co-activator-1α (PGC-1α) is a transcription co-activator for nuclear receptors such as the PPARs, and thereby coordinates a number of gene expression programs to promote mitochondrial biogenesis and oxidative phosphorylation. Studies of PGC-1α knock-out mice have yielded important insights into the role of PGC-1α in normal nervous system function and potentially neurological disease. HD is caused by a polyglutamine repeat expansion in the huntingtin protein, and decades of work have established mitochondrial dysfunction as a key feature of HD pathogenesis. However, after the discovery of the HD gene, numerous reports produced strong evidence for altered transcription in HD. In 2006, a series of studies revealed that PGC-1α transcription interference contributes to HD neurodegeneration, linking the nuclear transcriptionopathy with the mitochondrial dysfunction. Subsequent work has strengthened this view, and further extended the role of PGC-1α within the CNS. Within the last year, studies of Parkinson's disease, another involuntary movement disorder long associated with mitochondrial dysfunction, have shown that PGC-1α dysregulation is contributing to its pathogenesis. As PGC-1α is likely also important for aging, a process with considerable relevance to neuron function, translational studies aimed at developing therapies based upon the PGC-1α pathway as a high priority target are underway.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Taiji
authors.initials: T
authors.lastname: Tsunemi
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors
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