Fyn激酶调控Tau蛋白病变的播种效应和传播效应的机制研究

Tau蛋白病（Tauopathies）是一类以微管结合蛋白Tau的过度磷酸化和异常沉积为特征的神经退行性疾病，包括阿尔茨海默病（AD）、额颞叶痴呆等。过度磷酸化的“Tau种子”进入细胞后诱发内源性Tau发生聚合，通过突触在神经元和脑区间传递实现病理的传播，但介导这些播种和传播效应的关键分子尚不清楚。申请人前期工作发现酪氨酸激酶Fyn能促进Tau蛋白的合成和磷酸化修饰，从而介导AD中的Tau病变。近期研究又发现Fyn能显著促进Tau核心区段的聚集，可能与其激酶活性密切相关。此外，Fyn通过谷氨酸受体调节突触功能，且Fyn的SH2结构域能与Tau蛋白中磷酸化的酪氨酸结合。因此申请人推测Fyn同时调控Tau种子诱发的Tau聚集和细胞间的传播。本项目拟利用高灵敏度的生物感受器细胞，结合动物模型和体外实验，来阐述Fyn介导Tau病变播种和传播效应的分子机理，为Tau蛋白病的药物筛选提供理论依据。

Tauopathy is a type of neurodegenerative diseases characterized by hyperphosphorylation microtubule-binding protein Tau and its abnormal deposition, including Alzheimer's disease (AD), frontotemporal dementia, etc. Hyperphosphorylated "Tau seeds" induce endogenous Tau to aggregate after entering the cell, and transmit the pathology through synapses between neurons and brain regions, yet the key molecules that mediate these seeding and spreading effects are still unclear. The applicant's previous work revealed that tyrosine kinase Fyn can promote Tau protein synthesis and phosphorylation, thereby mediating Tau lesions in AD. Our recent studies have also found that Fyn can significantly promote the aggregation of Tau core segments, which may be closely related to its kinase activity. In addition, Fyn regulates synaptic function through glutamate receptors, and Fyn's SH2 domain can bind to phosphorylated tyrosine in Tau protein. Therefore, the applicant speculates that Fyn simultaneously regulates Tau aggregation and cell-to-cell transmission induced by Tau seeds. This project intends to use high-sensitivity biosensor cells, combined with animal models and in vitro experiments, to explain the molecular mechanism of Fyn-mediated Tau disease seeding and spreading effects, and provide a theoretical basis for drug screening for Tauopathies.