title: Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation.
abstract: We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Wang
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyata
authors.forename: Susan
authors.initials: S
authors.lastname: Klinedinst
authors.forename: Hwei-Ming
authors.initials: HM
authors.lastname: Peng
authors.forename: Jason P
authors.initials: JP
authors.lastname: Chua
authors.forename: Tomoko
authors.initials: T
authors.lastname: Komiyama
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morishima
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
authors.forename: William B
authors.initials: WB
authors.lastname: Pratt
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Osawa
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004330:Drosophila; D005260:Female; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000737:chemistry; D020966:Muscular Disorders, Atrophic / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009498:Neurotoxins; D010455:Peptides; D011506:Proteins; D011725:Pyridines; D011944:Receptors, Androgen; D013844:Thiazoles; C079109:N-(3-pyridylmethyl)adriamycin; C097188:polyglutamine; D004317:Doxorubicin; C097880:MKT 077