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Human Molecular Genetics Advance Access originally published online on February 6, 2006
Human Molecular Genetics 2006 15(6):1025-1041; doi:10.1093/hmg/ddl017
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin

Hongmin Wang1,{dagger}, Precious J. Lim1,2,{dagger}, Chaobo Yin1,{dagger}, Matthias Rieckher1, Bruce E. Vogel1,2 and Mervyn J. Monteiro1,2,*

1Medical Biotechnology Center, Institute for Neurodegenerative Diseases and 2Program in Molecular Medicine, University of Maryland Biotechnology Institute, 725 West Lombard Street, Baltimore, MD 21201, USA

* To whom correspondence should be addressed at: Medical Biotechnology Center, Institute for Neurodegenerative Diseases, Room N352, 725 West Lombard Street, Baltimore, MD 21201, USA. Tel: +1 4107068132; Fax: +1 4107068184; Email: monteiro{at}umbi.umd.edu

Received December 23, 2005; Accepted February 2, 2006

Expanded polyglutamine (polyQ) tracts are associated with the induction of protein aggregation and cause cytotoxicity in nine different neurodegenerative disorders. Here, we report that ubiquilin suppresses polyQ-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 polyQ-containing proteins and cell death induced by overexpression of a green fluorescent protein (GFP)–huntingtin fusion protein containing 74 polyQ 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). In 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 lines expressing GFP–Htt fusion proteins in body wall muscle displayed a polyQ repeat length-dependent decrease in body movement compared with 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 polyQ diseases.

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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