CHIP-ping away at tau

Citation metadata

Date: Mar. 2007
From: Journal of Clinical Investigation(Vol. 117, Issue 3)
Publisher: American Society for Clinical Investigation
Document Type: Article
Length: 2,057 words
Lexile Measure: 1400L

Document controls

Main content

Article Preview :

Protein accumulation is a hallmark of many neurodegenerative disorders. In Alzheimer's disease (AD), a hyperphosphorylated form of the protein tau (p-tau) forms intracellular inclusions known as neurofibrillary tangles. Deposits of p-tau have also been found in the brains of patients with Down's syndrome, supranuclear palsy, and prion disease. Mutations in tau have been causally associated with at least one inherited neurologic disorder, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), implying that tau abnormalities by themselves can be a primary cause of degenerative diseases of the CNS. Removal of these p-tau species may occur by both chaperone-mediated refolding and degradation. In this issue of the JCI, Dickey and colleagues show that a cochaperone protein, carboxyl terminus of Hsp70-interacting protein (CHIP), in a complex with Hsp90 plays an important role in the removal of p-tau (see the related article beginning on page 648). Pharmacologic manipulation of Hsp90 may be used to alleviate p-tau accumulation in disease.

Role of chaperones in degradation and refolding of abnormal tau

Chaperones are molecular machines designed to maintain proteins in a properly folded state (1). Misfolded proteins that cannot be refolded by chaperones are ubiquitinated and thereby targeted for degradation by the proteasome (2). It has been proposed that the chaperone and proteasome systems may act in concert in clearing abnormal tau and other proteins that accumulate in neurologic diseases (3). Indeed, in Alzheimer's disease (AD) brains, neurons with a higher content of the molecular chaperones Hsp70 or Hsp90 have fewer neurofibrillary tangles (NFTs; ref. 4). In a transgenic mouse model expressing a mutant version of human tau that is associated with the neurologic disorder frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), reduced levels of Hsp90 were detected in the hippocampi of affected animals (4). Conversely, inhibition of the proteasome in cells overexpressing parkin, a protein found in aggregates in Parkinson's disease patients, leads to parkin inclusion formation (5).

The chaperone cofactor proteins Hsp70-interacting protein (Hip) and Hsp70/Hsp90-organizing protein (Hop) both interact with Hsp70 via their tetratricopeptide repeat (TPR) domains. In a screen for additional TPR-encoding cDNAs, a protein named carboxyl terminus of Hsp70-interacting protein (CHIP) was identified (6). As its name suggests, CHIP interacts with Hsp70 and inhibits its ATPase activity, indicating that CHIP might be involved in an Hsp70-mediated process distinct from refolding (6). Hsp90, which binds CHIP via its TPR domain (7), is different from Hsp70 and other chaperones in that it does not act in nascent protein folding and most of its known substrates are signal transduction proteins. It is generally believed that Hsp90 binding follows the formation of an Hsp70/substrate complex (8). CHIP can interact with either Hsp70 or Hsp90 through the same TPR, displacing them from Hop or other TPR-containing proteins (7, 8).

CHIP has been shown to be an E3 ubiquitin ligase whose activity is dependent on Hsp90 or an Hsp70/40 complex (9). Petrucelli and colleagues previously showed that CHIP ubiquitinates tau in transfected cells and stimulates tau aggregation (10). Hsp70 upregulation attenuated tau aggregation concomitantly...

Source Citation

Source Citation   

Gale Document Number: GALE|A160592873