Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated.
Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated.
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DOI：
10.1016/j.bbrc.2016.08.053
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发表时间：
2016-09-16
影响因子：
3.1
通讯作者：
Iijima KM
中科院分区：
文献类型：
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作者：
Ando K;Oka M;Ohtake Y;Hayashishita M;Shimizu S;Hisanaga S;Iijima KM
微管相关蛋白tau的异常磷酸化在许多神经退行性疾病中观察到，包括阿尔茨海默病（AD）。PAR-1/MARK对两个tau残基Ser 262和Ser 356的AD相关磷酸化在代谢不良的初始阶段稳定tau，导致随后的磷酸化事件、积累和毒性。然而，这些位点中的每一个的磷酸化对tau稳定的相对贡献尚未阐明。在人类tau蛋白毒性的果蝇模型中，我们发现tau蛋白在Ser 262处磷酸化，但在Ser 356处不磷酸化，并且阻断Ser 262磷酸化降低了总tau蛋白水平。相比之下，当PAR-1与tau共过表达时，tau在Ser 262和Ser 356处过度磷酸化。在这些条件下，tau蛋白水平显著升高，并且必须防止两个残基处的tau磷酸化以完全抑制这种升高。这些结果表明，当PAR-1/MARK活性正常时，Ser 262处的tau磷酸化在tau稳定中起主要作用，而当PAR-1/MARK活性异常升高时，Ser 356磷酸化开始有助于这一过程，如在患病的大脑中。
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.
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HSP90-TAU复合物揭示了伴侣作用特异性的分子基础。
影响因子：
64.5
作者：
Karagöz GE;Duarte AM;Akoury E;Ippel H;Biernat J;Morán Luengo T;Radli M;Didenko T;Nordhues BA;Veprintsev DB;Dickey CA;Mandelkow E;Zweckstetter M;Boelens R;Madl T;Rüdiger SG
通讯作者：
Rüdiger SG
影响因子：
3.7
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
通讯作者：
Zhong Y
影响因子：
4.1
作者：
Litersky, JM;Johnson, GVW;Seubert, P
通讯作者：
Seubert, P
DOI：
10.1073/pnas.242720499
发表时间：
2003-01-21
影响因子：
11.1
作者：
Dou, F;Netzer, WJ;Xu, HX
通讯作者：
Xu, HX
影响因子：
16.6
作者：
通讯作者：
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