The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here, we show that the serine/threonine kinase GSK3β catalyzes the aggregation of the protein tau into Alzheimer’s disease (AD)-like filaments. We demonstrate that phosphorylation by GSK3β, but not by several other kinases, promotes the aggregation of full-length tau as well as enhances phase separation into gel-like condensate structures. Cryoelectron microscopy further reveals that the fibrils formed by GSK3β-phosphorylated tau adopt a fold comparable to that of paired helical filaments isolated from the brains of AD patients. Our results elucidate the intricate relationship between posttranslational modification and the formation of tau strains in neurodegenerative diseases.

中文翻译：

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GSK3β 磷酸化催化 tau 聚集成阿尔茨海默病样细丝


蛋白质的病理沉积是几种毁灭性神经退行性疾病的标志。这些病理沉积物由采用不同结构（称为菌株）的蛋白质聚集体组成。然而，导致形成不同聚集菌株的分子因素尚不清楚。在这里，我们表明丝氨酸/苏氨酸激酶 GSK3β 催化蛋白质 tau 聚集成阿尔茨海默病 （AD） 样细丝。我们证明，GSK3β 的磷酸化，而不是其他几种激酶的磷酸化，促进了全长 tau 的聚集，并增强了相分离成凝胶状凝聚物结构。冷冻电子显微镜进一步揭示，由 GSK3β 磷酸化 tau 形成的原纤维采用的折叠与从 AD 患者大脑中分离的成对螺旋丝的折叠相当。我们的结果阐明了神经退行性疾病中翻译后修饰与 tau 菌株形成之间的复杂关系。