Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model

BMC Neuroscience

Anna-Lena Ström¹  Ülo Langel¹  Staffan Lindberg¹  Xin Yu¹  Abiodun Ajayi¹ 

[1] Department of Neurochemistry, Stockholm University, Svante Arrhenius väg 21A, SE-106 91, Stockholm, Sweden

关键词: SCA7;    Polyglutamine;    Oxidative stress;    Neurodegeneration;    NADPH oxidase complex;    Ataxin-7;   

Others  :  1170622
DOI  :  10.1186/1471-2202-13-86

 received in 2012-03-15, accepted in 2012-07-11,  发布年份 2012

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2012 Ajayi et al.; licensee BioMed Central Ltd.

【 图 表 】

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