Sex-dependent effect of bag1 in HD mice

HD Lighthouse Contributing Editor's Comment: 

One question that often comes up in the HD community is whether HD varies in any way with gender. A new study finds gender differences in the HD mice.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 04-16-2008

Xiao-Jiang Li, M.D., Ph.D., Distinguished Professor of Human Genetics, Emory University

Sex-dependent effect of bag1 in ameliorating motor deficits of Huntington's disease transgenic mice

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

The pathogenesis of Huntington’s 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. Since 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 over-expressing BAG1 in neurons. Transgenic BAG1 significantly reduces the levels of mutant htt in synaptosomal fraction of male HD mice. Overexpression of BAG1 also 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.

Source: Journal of Biological Chemistry 2008 Apr 8 [Epub ahead of print]