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.

这是一项基本的基础研究建议，专注于了解BCL的作用在介导选择性自噬和tau的转移中，有2个相关的花道计3（BAG3）神经元以及这些过程在衰老期间的变化。选择性自噬是细胞的一部分蛋白质质量控制（PQC）系统，这是感官的蜂窝途径的集合受损的蛋白质并促进其去除。 PQC对于维护适当的功能补充细胞中蛋白质。 tau是一种神经元的富集多功能蛋白。鉴于tau在神经元功能中的重要性，了解调节磷酸-TAU物种以及总tau水平的PQC过程至关重要重要性。有选择性自噬的意识越来越多，即特定的识别将客户蛋白靶向开发的自噬体对于有效的PQC至关重要。伴侣和联合伴侣以及自噬机械是关键的PQC播放器识别和去除受损蛋白质的过程。联合伴侣Bag3是一个选择性自噬的重要参与者，因此是PQC系统中的关键播放器。最近我们提出了令人兴奋的发现，即在神经元中，Bag3在促进自噬并指导内源性的可溶性tau自动噬。这是基本重要性，因为在健康的神经元中，自噬是组成型活跃的，并且在维持功能蛋白质组方面起着重要作用。 BAG3是应力诱导的蛋白质在正常衰老期间增加。有人建议在变化期间细胞的需求增加了自噬来维持蛋白质稳态的使用，并且 BAG3在此过程中起着至关重要的作用。确实，已经记录了在衰老期间 BAG3水平在啮齿动物大脑同时增加，依赖性增加自噬用于蛋白质。因此，了解Bag3在自噬中的作用及其如何促进可溶性tau物种清除的功能具有基本意义。这该提议的总体假设是Bag3是选择性自噬的关键调解人神经元和在介导tau的清除率中起着重要作用。这个特定的目的建议是：（1）测试BAG3调节自噬和TAU更新的假设原位和体内，在老化的依赖性袋中促进自噬和tau间隙增加，（2）确定Bag3-的基本特征介导tau间隙的伴侣复合体，（3）以表征机制调节BAG3表达并测试其在基于自噬的tau中的作用在神经元中。目前，BAG3在介导神经元中的自噬中的作用知之甚少，以及它如何促进tau的营业额；此应用程序在我们的知识。