Tau triage decisions mediated by the chaperone network

Research output: Contribution to journalArticle

2 Citations (Scopus)

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)
Pages (from-to)145-151
Number of pages7
JournalAdvances in Alzheimer's Disease
Volume3
DOIs
StatePublished - 2012

Fingerprint

Triage
Tauopathies
Microtubule Proteins
Acetylation
Carrier Proteins
Brain
Research
Proteins
Therapeutics
Direction compound

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Tau triage decisions mediated by the chaperone network. / Cook, Casey; Petrucelli, Leonard.

In: Advances in Alzheimer's Disease, Vol. 3, 2012, p. 145-151.

Research output: Contribution to journalArticle

@article{ce5b607ebcdb458b83f8acd79356ded7,
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.",
keywords = "Alzheimer's disease, chaperone, CHIP, Hsp70, Hsp90, tau",
author = "Casey Cook and Leonard Petrucelli",
year = "2012",
doi = "10.3233/978-1-61499-154-0-145",
language = "English (US)",
volume = "3",
pages = "145--151",
journal = "Advances in Alzheimer's Disease",
issn = "2210-5727",
publisher = "IOS Press",

}

TY - JOUR

T1 - Tau triage decisions mediated by the chaperone network

AU - Cook, Casey

AU - Petrucelli, Leonard

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - chaperone

KW - CHIP

KW - Hsp70

KW - Hsp90

KW - tau

UR - http://www.scopus.com/inward/record.url?scp=84877978432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877978432&partnerID=8YFLogxK

U2 - 10.3233/978-1-61499-154-0-145

DO - 10.3233/978-1-61499-154-0-145

M3 - Article

AN - SCOPUS:84877978432

VL - 3

SP - 145

EP - 151

JO - Advances in Alzheimer's Disease

JF - Advances in Alzheimer's Disease

SN - 2210-5727

ER -