Investigating autophagic degradation of tau mediated by polyubiquitination

多泛素化介导的tau自噬降解研究 人脑中tau的异常降解和积累与 阿尔茨海默病(AD)的发展。现在，人们的注意力集中在细胞通路上 从神经细胞中清除tau，特别是通过自噬-溶酶体途径。K63链接 Tau的多泛素化与tau自噬降解的早期阶段密切相关。与.相比 更好地研究了tau的蛋白酶体降解、自噬机制对tau的识别以及 对溶酶体随后的降解知之甚少。机械细节和深入的生化 缺乏对个别参与者的描述和这一过程中的步骤。K63如何与 Tau的多泛素化介导其自噬降解在很大程度上是未知的。而且，我们的理解是 它对tau去泛素化的影响以及它在调节tau动态平衡中的作用仍然非常有限。我们将解决这些问题 使用使用半合成方法生成的K63-PolyUb-tau探针捕获和 识别同源自噬受体和脱泛素酶，它们负责调节自噬 牛磺酸的降解。我们的发现将揭示这一细胞过程中的新生物学，并提供潜在的新靶点 用于AD的药理干预。

Investigating autophagic degradation of tau mediated by polyubiquitination Aberrant degradation and accumulation of tau in human brains is intimately connected to the development of Alzheimer’s disease (AD). Attentions are now directed to the cellular pathways responsible for the clearance of tau from neuronal cells, particularly through the autophagy-lysosome pathway. K63-linked polyubiquitination of tau is intimately involved in the early stage of autophagic degradation of tau. Compared to the better studied proteasomal degradation of tau, the recognition of tau by the autophagic machinery and the subsequent degradation by lysosome is poorly understood. Mechanistic details and in-depth biochemical characterization of the individual players and steps in this process are lacking. How the K63-linked polyubiquitination of tau mediates its autophagic degradation is largely unknown. Moreover, our understanding of tau deubiquitination and its role in regulating tau homeostasis is still very limited. We will address these unanswered questions using K63-polyUb-tau probes generated using a semi-synthetic approach to capture and identify cognate autophagic receptors and deubiquitinases that are responsible for modulation of the autophagic degradation of tau. Our findings will unveil new biology in this cellular process and provide potential new targets for pharmacological intervention of AD.