The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.
J Clin Invest
; 117(3): 648-58, 2007 Mar.
Article
in En
| MEDLINE
| ID: mdl-17304350
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.
Full text:
1
Database:
MEDLINE
Main subject:
Tau Proteins
/
Molecular Chaperones
/
HSP90 Heat-Shock Proteins
/
Tauopathies
/
Ubiquitin-Protein Ligases
/
Alzheimer Disease
Type of study:
Prognostic_studies
Limits:
Aged
/
Aged80
/
Animals
/
Female
/
Humans
/
Male
Language:
En
Year:
2007
Type:
Article