title: Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model.
abstract: BACKGROUND
  Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s) of toxicity is still unclear.
  
  
  RESULTS
  In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX) complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress.
  
  
  CONCLUSIONS
  Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.
authors: Department of Neurochemistry, Stockholm University, Svante Arrhenius väg 21A, Stockholm, Sweden.
authors: Abiodun
authors: A
authors: Ajayi
authors: Xin
authors: X
authors: Yu
authors: Staffan
authors: S
authors: Lindberg
authors: Ulo
authors: U
authors: Langel
authors: Anna-Lena
authors: AL
authors: Ström
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010455:Peptides / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection / Q000379:methods
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D016877:Oxidants; D010455:Peptides; C539738:RORA protein, human; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D006861:Hydrogen Peroxide; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019255:NADPH Oxidases; D005982:Glutathione Transferase