The degradation of tau by selective autophagy

这是一项基础研究提案，重点是了解Bcl-2的作用， 2-相关的花基因3（BAG 3）介导选择性自噬和tau蛋白的周转， 以及这些过程在衰老过程中是如何变化的。选择性自噬是细胞 蛋白质质量控制（PQC）系统，它是细胞通路的集合， 破坏蛋白质并促进其去除。PQC对于维护 细胞中蛋白质的适当的、功能性的补充。Tau是一种神经富集的 多功能蛋白质考虑到tau蛋白在神经元功能中的重要性， 调节磷酸化tau种类以及总tau水平的PQC过程是至关重要的。 重要性越来越多的人意识到选择性自噬，即，的特异性识别 靶向客户蛋白的发展自噬体是必不可少的有效PQC。 伴侣和共同伴侣，沿着自噬机制，是PQC的关键参与者， 识别和去除受损蛋白质的过程。共陪伴蛋白BAG 3是一种 在选择性自噬的重要球员，因此在PQC系统的关键球员。最近 我们有了一个令人兴奋的发现，在神经元中，BAG 3在以下方面起着重要作用： 促进自噬并引导内源性可溶性tau蛋白自噬。这一点 因为在健康的神经元中，自噬是组成性活跃的， 在维持蛋白质组的功能方面起着重要作用。BAG 3是一种应激诱导蛋白 在正常衰老过程中会增加有人认为，在衰老过程中， 细胞的需求增加了自噬的使用，以维持蛋白质的稳态， BAG 3在这个过程中起着至关重要的作用。事实上，有文献记载， BAG 3水平在啮齿动物脑中增加，同时增加对 自噬的蛋白质稳定作用。因此，了解BAG 3在自噬中的作用以及它如何 促进可溶性tau种类清除的功能具有根本意义。的 该建议的总体假设是BAG 3是选择性自噬的关键介导剂， 神经元，并在介导tau的清除中起重要作用。具体目标是 我们的研究目的是：（1）验证BAG 3调节自噬和tau蛋白转换的假说 在原位和体内，以及在老化过程中，对BAG 3的依赖性，以促进 自噬和tau清除增加，（2）为了确定BAG 3的基本特征， 介导tau蛋白清除的分子伴侣复合物，和（3）表征机制 其调节BAG 3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。目前对BAG 3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;这个应用程序解决了我们的这些差距。 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.