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Human Molecular Genetics Advance Access published online on February 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl017
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 23, 2005
Revised February 2, 2006
Accepted February 2, 2006

Article

Suppression of Polyglutamine-Induced Toxicity in Cell and Animal Models of Huntington's Disease by Ubiquilin

Hongmin Wang 1, Precious J. Lim 2, Chaobo Yin 1, Matthias Rieckher 1, Bruce E. Vogel 2, and Mervyn J. Monteiro 3 *

1 Medical Biotechnology Center, Program in Neurodegenerative Diseases
2 Medical Biotechnology Center, Program in Neurodegenerative Diseases; Program in Molecular Medicine, University of Maryland Biotechnology Institute, 725 West Lombard Street, Baltimore, Maryland 21201
3 Medical Biotechnology Center, Program in Neurodegenerative Diseases, Institute for Neurodegenerative Diseases, Room N352; Program in Molecular Medicine, University of Maryland Biotechnology Institute, 725 West Lombard Street, Baltimore, Maryland 21201

* To whom correspondence should be addressed.
Mervyn J. Monteiro, E-mail: monteiro{at}umbi.umd.edu


  Abstract

Expanded polyglutamine tracts are associated with the induction of protein aggregation and cause cytotoxicity in nine different neurodegenerative disorders. Here, we report that ubiquilin suppresses polyglutamine-induced protein aggregation and toxicity in cells and in an animal model of Huntington's disease. Overexpression of ubiquilin in HeLa cells and primary neurons reduced aggregation of polyglutamine-containing proteins and cell death induced by overexpression of a GFP-Huntingtin-fusion protein containing 74 polyglutamine repeats (GFP-Htt(Q74)), in a dose-dependent manner. Moreover, overexpression of ubiquilin suppressed oxidative stress-induced cell death in HeLa cell lines stably expressing GFP-Htt(Q74). By contrast, knockdown of ubiquilin expression in these cell lines was associated with increases in DNA fragmentation, caspase activation, GFP-fusion protein aggregation, and cell death. Caenorhabditis elegans (C. elegans) lines expressing GFP-Htt-fusion proteins in body wall muscle displayed a polyglutamine repeat length-dependent decrease in body movement compared to wild-type animals. RNA interference of the C. elegans ubiquilin gene exacerbated the motility defect, whereas overexpression of ubiquilin prevented, and could rescue, loss of worm movement induced by overexpression of GFP-Htt(Q55). These results suggest that ubiquilin might be a novel therapeutic target for treating polyglutamine diseases.


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