Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species
| Autor: | Songsong Cao, Amber M.K. Clark, Judith Dunmore, Guy A. Caldwell, Cam Patterson, Christopher B. Eckman, Leonard Petrucelli, Wen Lang Lin, Chad A. Dickey, Wing C. Lee, Mei Yue, Dennis W. Dickson, Cynthia Zehr, Gemma West, Mike Hutton, Kim A. Caldwell |
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| Rok vydání: | 2006 |
| Předmět: |
Transcription
Genetic Ubiquitin-Protein Ligases Mutant Tau protein Hyperphosphorylation Apoptosis Nerve Tissue Proteins tau Proteins Caspase 3 Animals Genetically Modified Mice Mice Neurologic Mutants Ubiquitin Stress Physiological RNA interference Cell Line Tumor mental disorders Animals Humans HSP70 Heat-Shock Proteins RNA Messenger Phosphorylation Caenorhabditis elegans Caenorhabditis elegans Proteins Mice Knockout Neurons biology General Neuroscience Brain Articles Molecular biology Ubiquitin ligase Enzyme Activation Molecular Weight Caspases Mutation Synapses biology.protein Synuclein RNA Interference Gene Deletion |
| Zdroj: | The Journal of Neuroscience. 26:6985-6996 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0746-06.2006 |
| Popis: | 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 theMAPTgene 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, recentin vivoevidence 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 forCHIP(chn-1) inCaenorhabditis elegansand 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. |
| Databáze: | OpenAIRE |
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