Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Proteasome Function Is Inhibited by Polyglutamine-expanded Ataxin-1, the SCA1 Gene Product

  • Park, Yongjae (Graduate School of Biotechnology, Korea University) ;
  • Hong, Sunghoi (Graduate School of Biotechnology, Korea University) ;
  • Kim, Sung-Jo (Graduate School of Biotechnology, Korea University) ;
  • Kang, Seongman (Graduate School of Biotechnology, Korea University)
  • Received : 2004.07.19
  • Accepted : 2004.09.13
  • Published : 2005.02.28
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Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder caused by expansion of the polyglutamine tract in the SCA1 gene product, ataxin-1. Using d2EGFP, a short-lived enhanced green fluorescent protein, we investigated whether polyglutamine-expanded ataxin-1 affects the function of the proteasome, a cellular multicatalytic protease that degrades most misfolded proteins and regulatory proteins. In Western blot analysis and immunofluorescence experiments, d2EGFP was less degraded in HEK 293T cells transfected with ataxin-1(82Q) than in cells transfected with lacZ or empty vector controls. To test whether the stability of the d2EGFP protein was due to aggregation of ataxin-1, we constructed a plasmid carrying $ataxin-1-{\Delta}114$, lacking the self-association region (SAR), and examined degradation of the d2EGFP. Both the level of $ataxin-1-{\Delta}114$ aggregates and the amount of d2EGFP were drastically reduced in cells containing $ataxin-1-{\Delta}114$. Furthermore, d2EGFP localization experiments showed that polyglutamine-expanded ataxin-1 inhibited the general function of the proteasome activity. Taken together, these results demonstrate that polyglutamine-expanded ataxin-1 decreases the activity of the proteasome, implying that a disturbance in the ubiquitin-proteasome pathway is directly involved in the development of spinocerebellar ataxia type1.

Keywords

Acknowledgement

Supported by : Ministry of Health & Welfare

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