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

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 6

The unique cochaperone CHIP is essential for Hsp90 inhibitor–mediated tau degradation and regulates the levels of other chaperones as well as Hsp90.

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The unique cochaperone CHIP is essential for Hsp90 inhibitor–mediated ta...
(A) HeLa cells transfected with Hsp90 siRNA were subsequently transfected with V5-tau with or without myc-CHIP. Tau accumulated when Hsp90 expression was reduced; however, this accumulation was abrogated by CHIP and the amount of coimmunoprecipitated tau/CHIP complexes increased in the absence of Hsp90. (B) Chaperone protein levels were assessed in CHIP–/– brain tissue by Western blot analysis. The absence of CHIP and elevation in total tau levels were confirmed. Both Hsp40 and Hsp90 levels were decreased. In addition, the non–HSF1-mediated cochaperone, Hop, was also significantly decreased in CHIP–/– mice. P23 levels remained unchanged compared to GAPDH levels. (C) Quantification was assessed by standard densitometry. Error bars represent SD of the 4 CHIP–/– mice. **P < 0.01; ***P < 0.001 versus CHIP+/+.