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Biochim Biophys Acta. 2012 May;1822(5):664-74. doi: 10.1016/j.bbadis.2011.11.014. Epub 2011 Nov 23.

Antioxidants in Huntington's disease.

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Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA.


Huntington's disease (HD) is a prototypical neurodegenerative disease in which there is selective neuronal degeneration, which leads to progressive disability, manifesting itself as a movement disorder, with both psychiatric and cognitive impairment. The disease is caused by a cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene, which causes an expanded polyglutamine repeat in the huntingtin protein, resulting in a protein with a novel gain of function. The mutant huntingtin protein causes neuronal dysfunction and eventual cell death in which transcriptional impairment, excitotoxicity, oxidative damage, inflammation, apoptosis and mitochondrial dysfunction are all implicated. A critical transcriptional impairment may be impaired expression and function of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a master co-regulator of mitochondrial biogenesis and expression of antioxidant enzymes. A deficiency of PGC-1α leads to increased vulnerability to oxidative stress and to striatal degeneration. The extent and severity of the oxidative damage in HD are features well recognized but perhaps under-appreciated. Oxidative damage occurs to lipids, proteins and deoxyribonucleic acid (DNA), and it has been suggested that the latter may contribute to CAG repeat expansion during DNA repair [1]. A marked elevation of oxidized DNA bases occurs in patients' plasma, which may provide a biomarker of disease progression. Antioxidants are effective in slowing disease progression in transgenic mouse models of HD, and show promise in human clinical trials. Strategies to transcriptionally increase expression of antioxidant enzymes by modulating the Nrf-2/ARE pathway, or by increasing expression of PGC-1α hold great promise for developing new treatments to slow or halt the progression of HD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

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