title: Analysis of the tau-associated proteome reveals that exchange of Hsp70 for Hsp90 is involved in tau degradation.
abstract: The microtubule associated protein tau (MAPT/tau) aberrantly accumulates in 15 neurodegenerative diseases, termed tauopathies. One way to treat tauopathies may be to accelerate tau clearance, but the molecular mechanisms governing tau stability are not yet clear. We recently identified chemical probes that markedly accelerate the clearance of tau in cellular and animal models. In the current study, we used one of these probes in combination with immunoprecipitation and mass spectrometry to identify 48 proteins whose association with tau changes during the first 10 min after treatment. These proteins included known modifiers of tau proteotoxicity, such as ILF-2 (NFAT), ILF-3, and ataxin-2. A striking observation from the data set was that tau binding to heat shock protein 70 (Hsp70) decreased, whereas binding to Hsp90 significantly increased. Both chaperones have been linked to tau homeostasis, but their mechanisms have not been established. Using peptide arrays and binding assays, we found that Hsp70 and Hsp90 appeared to compete for binding to shared sites on tau. Further, the Hsp90-bound complex proved to be important in initiating tau clearance in cells. These results suggest that the relative levels of Hsp70 and Hsp90 may help determine whether tau is retained or degraded. Consistent with this model, analysis of reported microarray expression data from Alzheimer's disease patients and age-matched controls showed that the levels of Hsp90 are reduced in the diseased hippocampus. These studies suggest that Hsp70 and Hsp90 work together to coordinate tau homeostasis.
authors: Departments of Pathology, University of Michigan, Ann Arbor, Michigan 48103, United States.
authors: Andrea D
authors: AD
authors: Thompson
authors: K Matthew
authors: KM
authors: Scaglione
authors: John
authors: J
authors: Prensner
authors: Anne T
authors: AT
authors: Gillies
authors: Arul
authors: A
authors: Chinnaiyan
authors: Henry L
authors: HL
authors: Paulson
authors: Umesh K
authors: UK
authors: Jinwal
authors: Chad A
authors: CA
authors: Dickey
authors: Jason E
authors: JE
authors: Gestwicki
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D001667:Binding, Competitive; D001923:Brain Chemistry / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D020543:Proteome / Q000737:chemistry*; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D020543:Proteome; D016875:tau Proteins