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Sex-dependent effect of BAG1 in ameliorating motor deficits of Huntington disease transgenic mice.

TitleSex-dependent effect of BAG1 in ameliorating motor deficits of Huntington disease transgenic mice.
Publication TypeJournal Article
Year of Publication2008
AuthorsOrr AL, Huang S, Roberts MA, Reed JC, Li S, Li X-J
JournalJ Biol Chem
Volume283
Issue23
Pagination16027-36
Date Published2008 Jun 06
ISSN0021-9258
KeywordsAnimals, Disease Models, Animal, DNA-Binding Proteins, Female, HSP70 Heat-Shock Proteins, Huntingtin Protein, Huntington Disease, Male, Mice, Mice, Transgenic, Motor Activity, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Protein Folding, Protein Structure, Tertiary, Rats, Sex Characteristics, Transcription Factors
Abstract

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.

DOI10.1074/jbc.M710606200
Alternate JournalJ. Biol. Chem.
PubMed ID18400759
PubMed Central IDPMC2414304
Grant ListAG15393 / AG / NIA NIH HHS / United States
R01 NS041669 / NS / NINDS NIH HHS / United States
NS041669 / NS / NINDS NIH HHS / United States
R01 AG019206 / AG / NIA NIH HHS / United States
AG019206 / AG / NIA NIH HHS / United States
NS045106 / NS / NINDS NIH HHS / United States
CA6739 / CA / NCI NIH HHS / United States