title: Tau triage decisions mediated by the chaperone network.
abstract: The pathological accumulation of the microtubule-binding protein tau is linked to an increasing number of neurodegenerative conditions associated with aging, though the mechanisms by which tau accumulates in disease are unclear. In this review, we will summarize our previous research assessing the mechanism of action, as well as the therapeutic potential of Hsp90 inhibition for the treatment of tauopathies. Specifically, we describe the development of a high-throughput screening approach to identify and rank compounds, and demonstrate the selective elimination of aberrant p-tau species in the brain following treatment with an Hsp90 inhibitor. Additionally, we identify CHIP as an essential component of the Hsp90 chaperone complex that mediates tau degradation, and present evidence to suggest that CHIP functions to identify and sequester neurotoxic tau species. Finally, we discuss recent data identifying an additional mechanism by which CHIP modulates protein triage decisions involving Hsp90. Specifically, CHIP indirectly regulates Hsp90 chaperone activity by modulating steady-state levels of the Hsp90 deacetylase, HDAC6, thus influencing both the acetylation state and function of Hsp90. Thus future research directions will focus on the manipulation of this network to promote degradation of pathogenic tau species in disease.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Cook
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D016875:tau Proteins; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases