Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases
| Autor: | Shouqing Luo, Coralie Vacher, David C. Rubinsztein, Janet E. Davies |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities 0303 health sciences Huntingtin biology Activator (genetics) animal diseases Cyclin-dependent kinase 5 Mutant Cell Biology Cleavage (embryo) Molecular biology nervous system diseases 3. Good health 03 medical and health sciences 0302 clinical medicine nervous system Cyclin-dependent kinase mental disorders biology.protein Phosphorylation 030217 neurology & neurosurgery Caspase 030304 developmental biology |
| Zdroj: | Journal of Cell Biology. 169:647-656 |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.200412071 |
| Popis: | Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. Mutant htt toxicity is exposed after htt cleavage by caspases and other proteases release NH2-terminal fragments containing the polyQ expansion. Here, we show htt interacts and colocalizes with cdk5 in cellular membrane fractions. Cdk5 phosphorylates htt at Ser434, and this phosphorylation reduces caspase-mediated htt cleavage at residue 513. Reduced mutant htt cleavage resulting from cdk5 phosphorylation attenuated aggregate formation and toxicity in cells expressing the NH2-terminal 588 amino acids (htt588) of mutant htt. Cdk5 activity is reduced in the brains of HD transgenic mice compared with controls. This result can be accounted for by the polyQ-expanded htt fragments reducing the interaction between cdk5 and its activator p35. These data predict that the ability of cdk5 phosphorylation to protect against htt cleavage, aggregation, and toxicity is compromised in cells expressing toxic fragments of htt. |
| Databáze: | OpenAIRE |
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