Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated
| Autor: | Koichi M. Iijima, Sawako Shimizu, Mikiko Oka, Kanae Ando, Yosuke Ohtake, Shin-ichi Hisanaga, Motoki Hayashishita |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
inorganic chemicals Tau protein Biophysics tau Proteins Biochemistry environment and public health Article 03 medical and health sciences chemistry.chemical_compound Glycogen Synthase Kinase 3 Phosphoserine 0302 clinical medicine GSK-3 Alzheimer Disease mental disorders medicine Animals Drosophila Proteins Humans Phosphorylation Molecular Biology biology Protein Stability Neurodegeneration Cell Biology biology.organism_classification medicine.disease Cell biology enzymes and coenzymes (carbohydrates) Disease Models Animal 030104 developmental biology Drosophila melanogaster chemistry Amino Acid Substitution Toxicity biology.protein bacteria Alzheimer's disease 030217 neurology & neurosurgery |
| Zdroj: | Biochemical and biophysical research communications. 478(2) |
| ISSN: | 1090-2104 |
| Popis: | Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains. |
| Databáze: | OpenAIRE |
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