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J. Biol. Chem., Vol. 283, Issue 23, 16027-16036, June 6, 2008

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Sex-dependent Effect of BAG1 in Ameliorating Motor Deficits of Huntington Disease Transgenic Mice^*

Adam L. Orr, Shanshan Huang, Meredith A. Roberts, John C. Reed, Shihua Li, and Xiao-Jiang Li¹

From the Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322 and the Burnham Institute for Medical Research, La Jolla, California 92037

The pathogenesis of Huntington disease (HD) is attributed to the misfolding of huntingtin (htt) caused by an expanded polyglutamine (polyQ) domain. Considerable effort has been devoted to identifying molecules that can prevent or reduce htt misfolding and the associated neuropathology. Although overexpression of chaperones is known to reduce htt cytotoxicity in cellular models, only modest protection is seen with Hsp70 overexpression in HD mouse models. Because the activity of Hsp70 is modulated by co-chaperones, an interesting issue is whether the in vivo effects of chaperones on polyQ protein toxicity are dependent on other modulators. In the present study, we focused on BAG1, a co-chaperone that interacts with Hsp70 and regulates its activity. Of htt mice expressing the N171-82Q mutant, we found that male N171-82Q mice show a greater deficit in rotarod performance than female N171-82Q mice. This sex-dependent motor deficit was improved by crossing N171-82Q mice with transgenic mice overexpressing BAG1 in neurons. Transgenic BAG1 also reduces the levels of mutant htt in synaptosomal fraction of male HD mice. Overexpression of BAG1 augmented the effects of Hsp70 by reducing aggregation of mutant htt in cultured cells and improving neurite outgrowth in htt-transfected PC12 cells. These findings suggest that the effects of chaperones on HD pathology are influenced by both their modulators and sex-dependent factors.

Received for publication, December 31, 2007 , and in revised form, April 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AG019206, NS045106, CA6739, AG15393, and NS041669. 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 To whom correspondence should be addressed: Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-3290; Fax: 404-727-2949; E-mail: xiaoli{at}genetics.emory.edu.

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