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J. Biol. Chem., Vol. 283, Issue 12, 7648-7656, March 21, 2008

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E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity^*

Amit Mishra¹, Priyanka Dikshit¹, Sudarshana Purkayastha, Jaiprakash Sharma, Nobuyuki Nukina, and Nihar Ranjan Jana²

From the Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050 and the Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age-related neurodegenerative disorders including polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the polyglutamine protein aggregation and toxicity. Here we have identified another ubiquitin ligase, called E6-AP, which is able to promote the proteasomal degradation of misfolded polyglutamine proteins and suppress the polyglutamine protein aggregation and polyglutamine protein-induced cell death. E6-AP interacts with the soluble misfolded polyglutamine protein and associates with their aggregates in both cellular and transgenic mouse models. Partial knockdown of E6-AP enhances the rate of aggregate formation and cell death mediated by the polyglutamine protein. Finally, we have demonstrated the up-regulation of E6-AP in the expanded polyglutamine protein-expressing cells as well as cells exposed to proteasomal stress. These findings suggest that E6-AP is a critical mediator of the neuronal response to misfolded polyglutamine proteins and represents a potential therapeutic target in the polyglutamine diseases.

Received for publication, August 9, 2007 , and in revised form, January 17, 2008.

^* This work was supported in part by the Dept. of Biotechnology, Government of India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a research fellowship from the Council of Scientific and Industrial Research, Government of India. These authors contributed equally to this work.

² To whom correspondence should be addressed: Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050, India. Tel.: 91-124-2338922; Fax: 91-124-2338910; E-mail: nihar{at}nbrc.ac.in.

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