Tau triage decisions mediated by the chaperone network

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Scopus citations

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.

Original languageEnglish (US)
Title of host publicationAlzheimer'S Disease
Subtitle of host publicationAdvances For A New Century
EditorsGeorge Perry, Xiongwei Zhu, Mark Smith, Aaron Sorensen, Jesus Avila
Pages145-151
Number of pages7
DOIs
StatePublished - Dec 1 2012

Publication series

NameAdvances in Alzheimer's Disease
Volume3
ISSN (Print)2210-5727
ISSN (Electronic)2210-5735

Keywords

  • Alzheimer's disease
  • chaperone
  • CHIP
  • Hsp70
  • Hsp90
  • tau

ASJC Scopus subject areas

  • Clinical Neurology

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  • Cite this

    Cook, C., & Petrucelli, L. (2012). Tau triage decisions mediated by the chaperone network. In G. Perry, X. Zhu, M. Smith, A. Sorensen, & J. Avila (Eds.), Alzheimer'S Disease: Advances For A New Century (pp. 145-151). (Advances in Alzheimer's Disease; Vol. 3). https://doi.org/10.3233/978-1-61499-154-0-145