The degradation of tau by selective autophagy

选择性自噬降解 tau

基本信息

批准号：
9918995
负责人：
Gail V. W. Johnson
金额：
$ 39.68万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918995
关键词：
Adaptor Signaling Protein Address Affect Age Aging Autophagocytosis Autophagosome Awareness BCL2 gene Basic Science Binding Proteins Biology Brain Cell division Cells Client Collection Complement Complex Data Degradation Pathway Dependence Disease Elements Excision Exhibits Foundations Future Health In Situ Knowledge Maintenance Mediating Mediator of activation protein Microtubules Modeling Molecular Molecular Chaperones Nervous system structure Neurons Neurosciences Organism Pathway interactions Pharmacology Physiological Processes Play Process Prosencephalon Proteins Proteome Quality Control Regulation Research Research Proposals Resources Rodent Role Stress-Induced Protein Structure System Testing Vacuole base clinically relevant genetic approach in vivo interest member mouse model normal aging promoter proteostasis response small hairpin RNA tau Proteins tau conformation tau-1

项目摘要

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.

这是一项基础研究提案，重点是了解 Bcl- 的作用 2 相关 anthogene 3 (BAG3) 在介导选择性自噬和 tau 蛋白周转中的作用神经元以及这些过程在衰老过程中如何变化。选择性自噬是细胞的一部分蛋白质质量控制 (PQC) 系统，它是感知细胞通路的集合损坏蛋白质并促进其去除。 PQC 对于维护至关重要细胞中蛋白质的适当的、功能性的补充。 Tau 蛋白富含神经元多功能蛋白质。鉴于 tau 在神经元功能中的重要性，了解调节磷酸化 tau 物种以及总 tau 水平的 PQC 过程至关重要重要性。人们越来越认识到选择性自噬，即特异性识别将客户蛋白靶向正在发育的自噬体对于有效的 PQC 至关重要。伴侣和辅助伴侣以及自噬机制是 PQC 的关键参与者识别和去除受损蛋白质的过程。辅助伴侣 BAG3 是选择性自噬中的重要参与者，因此是 PQC 系统中的关键参与者。最近我们做出了令人兴奋的发现，BAG3 在神经元中发挥着重要作用促进自噬并引导内源性可溶性 tau 蛋白进行自噬。这是属于至关重要，因为在健康的神经元中，自噬是持续活跃的并且在维持功能性蛋白质组方面发挥着重要作用。 BAG3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，细胞需求增加了自噬的使用来维持蛋白质稳态，并且 BAG3在此过程中起着至关重要的作用。事实上，有文献记载，在衰老过程中啮齿类动物大脑中的 BAG3 水平增加，同时对药物的依赖性增加自噬促进蛋白质稳态。因此，了解 BAG3 在自噬中的作用及其如何发挥作用促进可溶性 tau 物质清除的功能具有根本意义。这该提议的总体假设是 BAG3 是选择性自噬的关键介质神经元并在介导 tau 清除中发挥重要作用。本次活动的具体目标建议是： (1) 检验 BAG3 调节自噬和 tau 更新的假设原位和体内，并且在衰老过程中对 BAG3 的依赖促进自噬和 tau 清除增加，(2) 确定 BAG3- 的基本特征介导 tau 清除的伴侣复合物，以及 (3) 表征机制调节 BAG3 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 蛋白的周转；该应用程序解决了我们的这些差距知识。