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J. Biol. Chem., Vol. 282, Issue 13, 10096-10103, March 30, 2007

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Ubiquitin-interacting Motifs Inhibit Aggregation of PolyQ-expanded Huntingtin^*

Stephanie L. H. Miller¹, Erica L. Scappini², and John O'Bryan³

From the Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709 and the Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612

Expansion of polyglutamine (polyQ) tracts within proteins underlies a number of neurodegenerative diseases, such as Huntington disease, Kennedy disease, and spinocerebellar ataxias. The resulting mutant proteins are unstable, forming insoluble aggregates that are associated with components of the ubiquitin system, including ubiquitin, ubiquitin-like proteins, and proteins that bind to ubiquitin. Given the presence of these ubiquitin-binding proteins in the insoluble aggregates, we examined whether heterologous expression of short motifs that bind ubiquitin, termed ubiquitin-interacting motifs (UIMs), altered the aggregation of polyQ-expanded huntingtin (Htt), the protein product of the Huntington disease gene. We found that a subset of UIMs associated with mutant Htt. The ability to interact with ubiquitin was necessary, but not sufficient, for interaction with mutant Htt. Furthermore, we found that expression of single, isolated UIMs inhibited aggregation of mutant Htt. These data suggest that isolated UIMs might serve as potential inhibitors of polyQ-aggregation in vivo.

Received for publication, December 5, 2006 , and in revised form, January 26, 2007.

^* This work was supported in part by funding from the Intramural Research Program of the National Institutes of Health and by start up funds from the University of Illinois at Chicago. 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 Present address: Neurology Dept., Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235-1634.

² Present address: Laboratory of Neurobiology, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709.

³ To whom correspondence should be addressed: Dept. of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott, Rm. E403, M/C 868, Chicago, IL 60612. Tel.: 312-996-6221; Fax: 312-996-1225; E-mail: obryanj{at}uic.edu.

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