Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease

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Title:	Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease
Authors:	謝明麗 Yu, Ya-Chun Kuo, Chen-Ling Cheng, Wen-Ling Liu, Chin-San Hsieh, Mingli
Contributors:	Tunghai University Vascular and Genomic Research Center, Department of Neurology China Medical University Hospital Chung Shan Medical University
Keywords:	Machado-Joseph disease antioxidant glutathione mitochondrial DNA
Date:	2009-06
Issue Date:	2016-07-20T01:48:57Z (UTC)
Publisher:	US:Wiley-Liss
Abstract:	Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the ataxin-3 protein that confers a toxic gain of function. Because of the late onset of the disease, we hypothesize that the accumulated oxidative stress or/and defective antioxidant enzyme ability may be contributory factors in the pathogenesis of MJD. In this study, we utilized SK-N-SH and COS7 cells stably transfected with full-length MJD with 78 polyglutamine repeats to examine any alterations in the antioxidant activity. We demonstrated a significant reduction in the ratio of GSH/GSSG and total glutathione content (GSH + 2x GSSG) in mutant MJD cells compared with the wild-type cells under normal or stressful conditions. We also showed that both SK-N-SH-MJD78 and COS7-MJD78-GFP cell lines have lower activities of catalase, glutathione reductase, and superoxide dismutase compared with the wild-type cell lines. In addition, it is known that, when cells are under oxidative stress, the mitochondrial DNA is prone to damage. Our results demonstrated that mitochondrial DNA copy numbers are decreased in mutant cells and SCA3 patients' samples compared with the normal controls. Furthermore, the amount of common mitochondrial DNA 4,977-bp deletion is higher in SCA3 patients compared with that in normal individuals. Overall, mutant ataxin-3 may influence the activity of enzymatic components to remove O(2)(-) and H(2)O(2) efficiently and promote mitochondrial DNA damage or depletion, which leads to dysfunction of mitochondria. Therefore, we suggest that the cell damage caused by greater oxidative stress in SCA3 mutant cells plays an important role, at least in part, in the disease progression.
Relation:	Journal of neuroscience research, 87(8), 1884-1891
Appears in Collections:	[生命科學系所] 期刊論文

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