Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
Current Address: Department of Chemistry, SRM Institute of Science and Technology, Chennai, TamilNadu, India.
Angew Chem Int Ed Engl. 2020 Mar 2;59(10):4059-4067. doi: 10.1002/anie.201913001. Epub 2020 Jan 28.
The consistent observation of phosphorylated tau in the pathology of Alzheimer's disease has contributed to the emergence of a model where hyperphosphorylation triggers both tau disassociation from microtubules and its subsequent aggregation. Herein, we applied a total chemical synthetic approach to site-specifically phosphorylate the microtubule binding repeat domain of tau (K18) at single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues. We show that hyperphosphorylation of K18 inhibits 1) its aggregation in vitro, 2) its seeding activity in cells, 3) its binding to microtubules, and 4) its ability to promote microtubule polymerization. The inhibition increased with increasing the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. Our results argue against the hyperphosphorylation hypothesis and underscore the importance of revisiting the role of site-specific hyperphosphorylation in regulating tau functions in health and disease.
阿尔茨海默病病理中磷酸化 tau 的持续观察促使出现了这样一种模型，即过度磷酸化既触发 tau 与微管解聚，又引发其随后的聚集。在此，我们采用全化学合成方法，在 tau 的微管结合重复结构域（K18）的单一（pS356）或多个（pS356/pS262 和 pS356/pS262/pS258）残基上进行定点磷酸化。我们发现 K18 的过度磷酸化抑制了 1）其在体外的聚集，2）其在细胞中的成核活性，3）其与微管的结合，以及 4）其促进微管聚合的能力。随着磷酸化位点数量的增加，抑制作用增强，S262 的磷酸化作用最强。我们的研究结果反对过度磷酸化假说，并强调有必要重新审视特定位点的过度磷酸化在调节 tau 健康和疾病中功能的作用。
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