In vivo evidence of CHIP up‐regulation attenuating tau aggregation

Abstract

The carboxyl terminus of heat-shock cognate (Hsc)70-interacting protein (CHIP) is a ubiquitin E3 ligase that can collaborate with molecular chaperones to facilitate protein folding and prevent protein aggregation. Previous studies showed that, together with heat-shock protein (Hsp)70, CHIP can regulate tau ubiquitination and degradation in a cell culture system. Ubiquitinated tau is one component in neurofibrillary tangles (NFTs), which are a major histopathological feature of Alzheimer's disease (AD). However, the precise sequence of events leading to NFT formation and the mechanisms involved remain unclear. To confirm CHIP's role in suppressing NFT formation in vivo, we performed a quantitative analysis of CHIP in human and mouse brains. We found increased levels of CHIP and Hsp70 in AD compared with normal controls. CHIP levels in both AD and controls corresponded directly to Hsp90 levels, but not to Hsp70 or Hsc70 levels. In AD samples, CHIP was inversely proportional to sarkosyl-insoluble tau accumulation. In a JNPL3 mouse brain tauopathy model, CHIP was widely distributed but weakly expressed in spinal cord, which was the most prominent region for tau inclusions and neuronal loss. Protein levels of CHIP in cerebellar regions of JNPL3 mice were significantly higher than in non-transgenic littermates. Human tau was more highly expressed in this region of mouse brains, but only moderate levels of sarkosyl-insoluble tau were detected. This was confirmed when increased insoluble tau accumulation was found in mice lacking CHIP. These findings suggest that increases in CHIP may protect against NFT formation in the early stages of AD. If confirmed, this would indicate that the quality-control machinery in a neuron might play an important role in retarding the pathogenesis of tauopathies.

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

“…5a Lower). The presence of the C terminus of heat-shock cognate 70-interacting protein, an ubiquitin E3 ligase found to collaborate with molecular chaperones in facilitating protein folding, was also identified in the Hsp90 complex, in agreement with findings of Sahara et al (39). An Hsp90 antibody specifically identified the chaperone in complex with p35 and its kinase partner cdk5 (Fig.…”

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

“…Very recently, it was demonstrated that aggregated tau species isolated from AD brain tissue by immunoprecipitation with a conformationspecific antibody were, in fact, polyubiquitinated at lysine residues near or within the microtubule binding region (Cripps et al, 2006), suggesting that these sites are not only critical for tau degradation but perhaps have a role in microtubule dynamics. These findings correlate well with the recent finding that CHIP levels were elevated in AD samples relative to control tissue (Sahara et al, 2005), further suggesting that CHIP plays an important role in mature tangle formation. Additionally, a recent proteomic study identified HSP70, HSP90, and tau as CHIP binding partners (Bomar et al, 2003;Grelle et al, 2006).…”

“…We then performed a coimmunoprecipitation experiment on brain homogenates from CHIP Ϫ/Ϫ , CHIP ϩ/ϩ , and JNPL3 mutant P301L tau mice [as a phospho-tau positive control (Lewis et al, 2000;Sahara et al, 2005)]. Although accumulation of ubiquitinated tau at 1 month of age in mice is normally very low, there were slight indications that more ubiquitinpositive tau was present in the CHIP ϩ/ϩ mice compared with CHIP Ϫ/Ϫ mice; however, more striking was the absence of Ϫ/Ϫ mice, with age-matched wild-type littermates (n ϭ 2), and homogenized for SDS-PAGE.…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…176 The HSP70 co-chaperone CHIP (the acronym stands for the carboxyl terminus of the Hsc70-interacting protein) functions as the primary E3-ligase in ubiquitin-dependent tau clearance. [177][178][179][180] In line with the important function of CHIP in tau clearance, increased tau accumulation was reported in CHIP knock-out mice. 178 Activation of the co-chaperone CHIP could prove to be an attractive drug target, especially because it also stabilizes full length APP against secretase cleavage.…”