Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy
| Autor: | Yosuke Ohtake, Taro Saito, Sawako Shimizu, Kanae Ando, Naoki Fujisaki, Shin-ichi Hisanaga, Koichi M. Iijima, Mikiko Oka, Akiko Maruko-Otake |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Tau protein tau Proteins Microtubules environment and public health Biochemistry Animals Genetically Modified Pathogenesis 03 medical and health sciences Cytosol Ca2+/calmodulin-dependent protein kinase mental disorders medicine Animals Amino Acid Sequence Phosphorylation Molecular Biology Gene knockdown biology Kinase Chemistry musculoskeletal neural and ocular physiology Neurodegeneration Regular Papers General Medicine medicine.disease Cell biology Protein Transport enzymes and coenzymes (carbohydrates) Drosophila melanogaster 030104 developmental biology Nerve Degeneration cardiovascular system biology.protein Female Tauopathy Calcium-Calmodulin-Dependent Protein Kinase Type 2 |
| Zdroj: | The Journal of Biochemistry. 162:335-342 |
| ISSN: | 1756-2651 0021-924X |
| DOI: | 10.1093/jb/mvx038 |
| Popis: | Abnormal deposition of the microtubule-associated protein tau is a common pathological feature of multiple neurodegenerative diseases, including Alzheimer's disease (AD), and plays critical roles in their pathogenesis. Disruption of calcium homeostasis and the downstream kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) coincides with pathological phosphorylation of tau in AD brains. However, it remains unclear whether and how dysregulation of CaMKII affects tau toxicity. Using a Drosophila model, we found that CaMKII promotes neurodegeneration caused by tau phosphorylated at the AD-associated sites Ser262/356. Overexpression of CaMKII promoted, while RNA-mediated knockdown of CaMKII and inhibition of CaMKII activity by expression of an inhibitory peptide suppressed, tau-mediated neurodegeneration. Blocking tau phosphorylation at Ser262/356 by alanine substitutions suppressed promotion of tau toxicity by CaMKII, suggesting that tau phosphorylation at these sites is required for this phenomenon. However, neither knockdown nor overexpression of CaMKII affected tau phosphorylation levels at Ser262/356, suggesting that CaMKII is not directly involved in tau phosphorylation at Ser262/356 in this model. These results suggest that a pathological cascade of events, including elevated levels of tau phosphorylated at Ser262/356 and aberrant activation of CaMKII, work in concert to promote tau-mediated neurodegeneration. |
| Databáze: | OpenAIRE |
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