The degradation of tau by selective autophagy

这是一项基础性的基础研究建议，重点是了解Bc l-1的作用。 2相关三茂铁基因(BAG3)在介导选择性自噬和tau周转中的作用 以及这些过程在衰老过程中的变化。选择性自噬是细胞 蛋白质质量控制(PQC)系统，它是细胞信号通路的集合 损坏的蛋白质，并促进它们的去除。PQC对于维护 细胞中适当的、有功能的蛋白质补体。Tau是一种富含神经元的 多功能蛋白质。鉴于tau在神经元功能中的重要性，理解 调节磷酸化tau种类和总tau水平的pqc过程是至关重要的。 重要性。人们越来越意识到选择性自噬，即特定的识别 而将客户蛋白定位于发育中的自噬小体是有效的PQC的关键。 伴随着自噬机制的是PQC中关键的PQC角色 识别和去除受损蛋白质的过程。共同监护人BAG3是一位 在选择性自噬中的重要角色，因此是PQC系统中的关键角色。最近 我们有了一个令人兴奋的发现，在神经元中，BAG3在 促进自噬并引导内源性、可溶的tau进入自噬。这是 基本的重要性，因为在健康的神经元中，自噬是结构性活跃的 在维持功能蛋白质组中起着重要作用。BAG3是一种应激诱导蛋白 在正常衰老过程中，这一比例会增加。有人提出，在老化过程中， 细胞需求增加了自噬的使用，以维持蛋白质的动态平衡， BAG3在这一过程中起着至关重要的作用。事实上，已经有记录表明，在衰老过程中 啮齿类动物大脑中BAG3水平增加的同时，对 蛋白抑制的自噬作用。因此，了解BAG3在自噬中的作用以及它是如何 促进可溶性tau物种清除的功能具有基础性意义。这个 这一提议的总体假设是，BAG3是选择性自噬的关键调节因子 并且在调节tau的清除中起着重要作用。这样做的具体目的是 建议是：(1)检验BAG3调节自噬和tau周转的假设 在体内和原位，以及在衰老过程中对BAG3的依赖 自噬和tau清除增加，(2)确定BAG3的基本特征- 调节tau清除的伴侣复合体，以及(3)表征机制 调节BAG3的表达并测试它们在基于自噬的tau清除中的作用 在神经元中。目前关于BAG3在介导神经元自噬中的作用知之甚少。 以及它如何促进tau的周转；此应用程序解决了我们的 知识。

This is a fundamental basic research proposal that is focused on understanding the role of Bcl- 2-associated anthogene 3 (BAG3) in mediating selective autophagy and the turnover of tau in neurons and how these processes change during aging. Selective autophagy is part of a cell's protein quality control (PQC) system, which is the collection of cellular pathways that sense damaged proteins and facilitate their removal. PQC is essential for the maintenance of the appropriate, functional complement of proteins in a cell. Tau is a neuronally enriched multifunctional protein. Given the importance of tau in neuronal function, understanding the PQC processes which regulate phospho-tau species, as well as total tau levels, is of critical importance. There is a growing awareness that selective autophagy, i.e., the specific recognition and targeting of client proteins to the developing autophagosome is essential for effective PQC. Chaperones and co-chaperones, along with the autophagic machinery, are key PQC players in the process of recognizing and removing damaged proteins. The co-chaperone BAG3 is an important player in selective autophagy and thus a pivotal player in the PQC system. Recently we made the exciting discovery that in neurons BAG3 plays a significant role in facilitating autophagy and directing endogenous, soluble tau to autophagy. This is of fundamental importance because in healthy neurons autophagy is constitutively active and plays a significant role in maintaining a functional proteome. BAG3 is a stress-induced protein that increases during normal aging. It has been suggested that during aging the change in cellular demands increases the use of autophagy to maintain protein homeostasis, and that BAG3 plays an essential role in this process. Indeed, it has been documented that during aging BAG3 levels increase in the rodent brain concurrent with an increased dependence on autophagy for proteostasis. Therefore, understanding the role of BAG3 in autophagy and how it functions to facilitate the clearance of soluble tau species is of fundamental significance. The overall hypothesis of this proposal is that BAG3 is a key mediator of selective autophagy in neurons and plays a significant role in mediating the clearance of tau. The specific aims of this proposal are: (1) To test the hypothesis that BAG3 modulates autophagy and tau turnover in situ and in vivo, and that during aging the dependence on BAG3 to facilitate autophagy and tau clearance increases, (2) To identify essential features of the BAG3- chaperone complex that mediate tau clearance, and (3) To characterize the mechanisms that regulate BAG3 expression and tests their role in autophagy-based clearance of tau in neurons. Currently little is known about the role of BAG3 in mediating autophagy in neurons, as well as how it facilitates the turnover of tau; this application addresses these gaps in our knowledge.