title: Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation.
abstract: The abnormal accumulation of the microtubule-binding protein tau is associated with a number of neurodegenerative conditions, and correlates with cognitive decline in Alzheimer's disease. The ubiquitin ligase carboxy terminus of Hsp70-interacting protein (CHIP) and the molecular chaperone Hsp90 are implicated in protein triage decisions involving tau, and have consequently been targeted for therapeutic approaches aimed at decreasing tau burden. Here, we present evidence that CHIP binds, ubiquitinates and regulates expression of histone deacetylase 6 (HDAC6). As the deacetylase for Hsp90, HDAC6 modulates Hsp90 function and determines the favorability of refolding versus degradation of Hsp90 client proteins. Moreover, we demonstrate that HDAC6 levels positively correlate with tau burden, while a decrease in HDAC6 activity or expression promotes tau clearance. Consistent with previous research on Hsp90 clients in cancer, we provide evidence that a loss of HDAC6 activity augments the efficacy of an Hsp90 inhibitor and drives client degradation, in this case tau. Therefore, our current findings not only identify HDAC6 as a critical factor for the regulation of tau levels, but also indicate that a multi-faceted treatment approach could more effectively arrest tau accumulation in disease.
authors.affiliation: Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Cook
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Kristyn
authors.initials: K
authors.lastname: Scheffel
authors.forename: Yari
authors.initials: Y
authors.lastname: Carlomagno
authors.forename: Judy
authors.initials: J
authors.lastname: Dunmore
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; D016875:tau Proteins; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases