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.
Huntington disease (HD)2 is an inherited neurodegenerative disease caused by a polyglutamine (polyQ) repeat expansion near the N terminus of the protein huntingtin (htt) (HD collaborative research group (49). Patients with HD suffer an array of cognitive, psychiatric, and motor disorders before death, which typically occurs 10 -20 years after onset of symptoms. Pathological hallmarks of this disease include selective neuronal loss and htt inclusions or aggregates that are formed in neuronal nuclei and processes (1, 2). Several genetic mouse models of HD have been developed, and they recapitulate various aspects of the disease observed in patients, including age-dependent inclusion formation and behavioral abnormalities (3). Of these mouse models, the transgenic N171-82Q model, which was generated by using the mouse prion promoter to drive neuronal expression of N-terminal mutant htt, exhibits progressive inclusion formation, motor deficits, weight loss, and shortened life-span (4). The well characterized phenotypes of HD transgenic mice have proven valuable for evaluating potential therapeutics.Misfolding of mutant htt is thought to contribute to abnormal protein-protein interactions, inclusion formation, and neuronal death. Currently, no treatment exists for those afflicted with HD, although considerable attention has been given to molecules that might alleviate the burden of misfolded htt. The major cytosolic chaperones of the Hsp40 and Hsp70 families act in concert to recognize misfolded proteins and refold them. Hsp70 family members interact with mutant N-terminal htt fragments and localize to incl...