Ando Kanae, Oka Mikiko, Ohtake Yosuke, Hayashishita Motoki, Shimizu Sawako, Hisanaga Shin-Ichi, Iijima Koichi M
Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan.
Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan.
Biochem Biophys Res Commun. 2016 Sep 16;478(2):929-34. doi: 10.1016/j.bbrc.2016.08.053. Epub 2016 Aug 9.
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.
在包括阿尔茨海默病（AD）在内的许多神经退行性疾病中，都观察到微管相关蛋白tau的异常磷酸化。PAR-1/MARK对tau的两个残基Ser262和Ser356进行的与AD相关的磷酸化，在代谢紊乱的初始阶段使tau稳定，导致随后的磷酸化事件、积累和毒性。然而，这些位点各自的磷酸化对tau稳定的相对贡献尚未阐明。在人类tau毒性的果蝇模型中，我们发现tau在Ser262处被磷酸化，但在Ser356处未被磷酸化，并且阻断Ser262磷酸化会降低总tau水平。相比之下，当PAR-1与tau共过表达时，tau在Ser262和Ser356处均被过度磷酸化。在这些条件下，tau的蛋白水平显著升高，并且防止这两个残基的tau磷酸化对于完全抑制这种升高是必要的。这些结果表明，当PAR-1/MARK活性正常时，Ser262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，如在患病大脑中，Ser356磷酸化开始对这一过程起作用。
