Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species
العنوان: | Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species |
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المؤلفون: | 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 |
المصدر: | The Journal of Neuroscience. 26:6985-6996 |
بيانات النشر: | Society for Neuroscience, 2006. |
سنة النشر: | 2006 |
مصطلحات موضوعية: | 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 |
الوصف: | 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. |
تدمد: | 1529-2401 0270-6474 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9eb312c980d78d26701f64f48fedce33 https://doi.org/10.1523/jneurosci.0746-06.2006 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....9eb312c980d78d26701f64f48fedce33 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 15292401 02706474 |
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