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J. Biol. Chem., Vol. 281, Issue 47, 36198-36204, November 24, 2006

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Context-dependent Dysregulation of Transcription by Mutant Huntingtin^*

From the Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments.

Received for publication, August 16, 2006 , and in revised form, September 22, 2006.

^* This work was supported by National Institute of Health Grants NS045016 (to S.-H. L.), NS41669 and AG19206 (to X.-J. L.). 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.

¹ To whom correspondence may be addressed: 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-3290; Fax: 404-727-3949; E-mail: xiaoli{at}genetics.emory.edu.

² To whom correspondence may be addressed. E-mail: shihual{at}genetics.emory.edu.

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