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

Abstract

Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitinnegative, hyperphosphorylated tau species. CHIP Ϫ/Ϫ mice also have increased neuronal caspase-3 levels and activity, as well as caspasecleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP Ϫ/Ϫ mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in postdevelopmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.

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.…”

“…[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. In addition, CHIP directs APP to proteasomal degradation, by promoting APP ubiquitination.…”

Akt and CHIP coregulate tau degradation through coordinated interactions

“…CHIP is a ubiquitin ligase that is essential for mitigating stress-related proteins after a cellular stress response (1,2). CHIP binds with both Hsp70 and Hsp90 and thus has an opportunity to interact with and degrade a number of proteins through the Hsp70 or Hsp90 scaffold.…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…In addition, the ubiquitin ligase UBE3A (ubiquitin protein ligase E3A) destabilizes p53, the heterozygous ablation of which causes significant memory loss and dementia phenotypes among genetically engineered mice (Jiang, Armstrong, Albrecht, Atkins, & Noebels, 1998). CHIP, a tau protein E3 ligase, functions to clear phosphorylated tau in neurons, and deletion of CHIP correspondingly results in the accumulation of hyperphosphorylated tau protein and facilitates the progression of AD (Dickey, Yue, Lin, Dickson, & Dunmore, 2006). In addition, FBW7, a constitutive substrate receptor for Cullin 1‐RING E3 ligases, displays critical involvement in neural development as its conditional knockout in neural stem cells leads to impaired differentiation and neuronal loss (Wang, Inuzuka, Fukushima, Wan, & Gao, 2011).…”