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

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 1

EC102 crosses the blood-brain barrier and reduces tau levels in cells after 24 hours.

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EC102 crosses the blood-brain barrier and reduces tau levels in cells af...
(A) CD-1 mice were injected i.p. with the indicated doses of EC102 and harvested 1, 3, 6, and 24 hours after injection. Brain levels of EC102 were assessed by HPLC analysis. Greater than 50% concentration was maintained for 3 hours with 200 mg/kg without detectable toxicity. (B) CD-1 mice were injected i.p. with 200 mg/kg EC102 or equivalent vehicle control (Con) to demonstrate the latency in Hsp70 induction following Hsp90 inhibition. After 6 hours, a slight increase in Hsp70 levels was observed in EC102-treated brain tissue, followed by a robust induction at 24 hours compared with vehicle-treated brain tissue. (C) HeLa cells overexpressing V5-tau were treated with a 1-μM concentration of EC102 for the indicated time points. p-tau, Hsp70, and GAPDH levels were assessed by Western blot. p-tau levels were modestly decreased 6 hours after treatment, with maximal reduction seen at 24 hours after treatment. Hsp70 levels were increased in a time-dependent manner. (D) In-cell Western analysis showed that 60%–65% of total tau was converted to p-tau in HeLa cells 24 hours after transfection with V5-tau.