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

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, Michael Hutton, Francis Burrows, Leonard Petrucelli

Research output: Contribution to journalArticle

448 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)648-658
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Dickey, C. A., Kamal, A., Lundgren, K., Klosak, N., Bailey, R. M., Dunmore, J., Ash, P., Shoraka, S., Zlatkovic, J., Eckman, C. B., Patterson, C., Dickson, D. W., Nahman, N. S., Hutton, M., Burrows, F., & Petrucelli, L. (2007). The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. Journal of Clinical Investigation, 117(3), 648-658. https://doi.org/10.1172/JCI29715