Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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

http://www.ncbi.nlm.nih.gov/pubmed/17304350

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.

Pubmed ID: 17304350 RIS Download

Mesh terms: Aged | Aged, 80 and over | Alzheimer Disease | Animals | Blood-Brain Barrier | DNA-Binding Proteins | Disease Models, Animal | Female | HSP90 Heat-Shock Proteins | Humans | Male | Mice | Molecular Chaperones | Phosphorylation | Protein Folding | RNA, Small Interfering | Serine | Tauopathies | Transcription Factors | Ubiquitin-Protein Ligases | tau Proteins