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The degradation of tau by selective autophagy

选择性自噬降解 tau

基本信息

批准号：
9395850
负责人：
Gail V. W. Johnson
金额：
$ 33.69万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9395850
关键词：
Adaptor Signaling Protein Address Affect Age Aging Alpha Cell 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 Vitronectin base clinically relevant genetic approach in vivo interest member mouse model normal aging promoter proteostasis response small hairpin RNA tau Proteins tau conformation

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.

这是一项基础研究计划，重点是了解Bcl-的作用