Li Yingjie, Qi Wending, Chen Le, Chu Fan, Jiang Wenfeng, Xu Zifeng, Luo Yuexin, Hu Xubo, Götz Jürgen, Li Chuanzhou
Department of Medical Genetics, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Acta Neuropathol. 2025 May 14;149(1):48. doi: 10.1007/s00401-025-02887-2.
Tau seeding and propagation are defining features of all tauopathies, including Alzheimer's disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive Tau pathology in the mouse brain and enhances Tau seeding induced by pathological Tau seeds in biosensor cells. However, even in the absence of seeds, Fyn itself, via its palmitoylation, triggers the de novo formation of small, plasma membrane-anchored Tau microclusters, which initiate pronounced and diverse intra- and transcellular Tau seeding in vitro and in vivo. Mechanistically, membrane-associated Fyn phosphorylates Tau at its Tyr310 epitope and then recruits and activates GSK3β locally, which further phosphorylates Tau at Ser/Thr sites in the microclusters, eliciting their full seeding capacity. Our data suggest that Fyn not only serves as a master switch that initiates Tau pathogenesis on its own, but also augments a pre-existing Tau pathology, leading to a vicious cycle of Tau aggregation.
tau蛋白种子形成和传播是包括阿尔茨海默病在内的所有tau蛋白病的决定性特征，但其潜在的分子驱动因素仍未完全明确。在此，我们揭示Fyn的表达会在小鼠大脑中促进大量tau蛋白病理变化，并增强生物传感器细胞中病理性tau蛋白种子诱导的tau蛋白种子形成。然而，即使在没有种子的情况下，Fyn自身通过其棕榈酰化作用，也会触发小的、锚定在质膜上的tau蛋白微聚集体的从头形成，这些微聚集体在体外和体内引发明显且多样的细胞内和细胞间tau蛋白种子形成。从机制上讲，与膜相关的Fyn在Tau的Tyr310表位处使其磷酸化，然后在局部募集并激活GSK3β，后者进一步使微聚集体中的Tau在丝氨酸/苏氨酸位点磷酸化，引发其完全的种子形成能力。我们的数据表明，Fyn不仅是一个自行启动tau蛋白发病机制的主开关，还会加剧已有的tau蛋白病理变化，导致tau蛋白聚集的恶性循环。
