Journal
JOURNAL OF NEUROSCIENCE
Volume 26, Issue 26, Pages 6985-6996Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0746-06.2006
Keywords
Parkinson's disease; CHIP; synuclein; Alzheimer's disease; ubiquitination; proteasome degradation; neuronal cell death
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Funding
- NIA NIH HHS [P01-AG17216] Funding Source: Medline
- NINDS NIH HHS [P50-NS40256] Funding Source: Medline
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Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurode-generative 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, ubiquitin-negative, hyperphosphorylated tau species. CHIP-/- mice also have increased neuronal caspase-3 levels and activity, as well as caspase-cleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP-/- 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.
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