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The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins
Chad A. Dickey, … , Francis Burrows, Leonard Petrucelli
Chad A. Dickey, … , Francis Burrows, Leonard Petrucelli
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):648-658. https://doi.org/10.1172/JCI29715.
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Research Article Article has an altmetric score of 24

The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

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Abstract

A primary pathologic component of Alzheimer’s disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70–interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.

Authors

Chad A. Dickey, Adeela Kamal, Karen Lundgren, Natalia Klosak, Rachel M. Bailey, Judith Dunmore, Peter Ash, Sareh Shoraka, Jelena Zlatkovic, Christopher B. Eckman, Cam Patterson, Dennis W. Dickson, N. Stanley Nahman Jr., Michael Hutton, Francis Burrows, Leonard Petrucelli

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Figure 5

Other components of the constitutive chaperone system are required to facilitate degradation of aberrant tau species by Hsp90 inhibitors; in turn, refolding machinery prevents p-tau degradation.

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Other components of the constitutive chaperone system are required to fa...
(A) HeLa cells were transfected in duplicate with nonsilencing control, CHIP, Hop, Hsp40, or Hsp70 siRNA pools for 72 hours, then transfected with V5-tau and harvested after 24 hours’ EC102 exposure. EC102 caused robust reductions in p-tau immunoreactivity in control-transfected cells, while chaperone knockdown prevented such reductions. (B) Densitometric values, shown as percent optical density of nontransfected, vehicle-treated (Veh) control cells after GAPDH normalization (dashed line). (C) P23 and Pin1 siRNA pools mimicked EC102 treatment. P23 knockdown reduced tau to an extent similar to that of EC102, whereas Pin1 knockdown reduced p-tau levels by nearly 75%. These siRNAs had no apparent effect on drug efficacy. (D) Effects of chaperone knockdown on total tau levels regardless of EC102 treatment were assessed by V5 immunoreactivity (including Hsp90 and HSF1 from Figure 4A). Densitometric values are shown as percent optical density of V5 immunoreactivity in nonsilencing siRNA–transfected cells after GAPDH normalization. Hsp90, CHIP, Hop, and Hsp40 all caused tau levels to accumulate by approximately 40%. HSF1 and Hsp70 had no effect on tau accumulation. P23 and Pin1 reduced total tau by approximately 35% and 75%, respectively. (E) These results suggest that dephosphorylation and refolding of p-tau is initially facilitated by an Hsp90/P23/Pin1 complex, preventing degradation; however, when refolding is subverted by Hsp90 inhibition or P23/Pin1 knockdown, p-tau is transferred to the Hsp70/CHIP complex, and polyubiquitination mediates degradation.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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