BAG3 regulates Rab35 and the ESCRT/endolysosome pathway

BAG3 调节 Rab35 和 ESCRT/内溶酶体途径

基本信息

批准号：
10667539
负责人：
Gail V. W. Johnson
金额：
$ 43.63万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667539
关键词：
Aftercare Alzheimer&apos s Disease Area Autophagocytosis Awareness BCL2 gene Binding Client DNA cassette Data Dendritic Spines Development Disease Endosomes Enterobacteria phage P1 Cre recombinase Esters Event Functional disorder GTPase-Activating Proteins Health Homeostasis Injections Investigation Kinetics Leucine LoxP-flanked allele Lysosomes Maintenance Mediating Mediator Molecular Morphology Mus Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathologic Pathology Pathway interactions Pattern Physiological Processes Play Population Process Proteins Proteome Proteomics Quality Control Reactive Oxygen Species Regulation Reporting Resistance Role Signal Transduction Sorting Stress Structure Synapses System Tamoxifen Tertiary Protein Structure Testing Vesicle high resolution imaging in vivo innovation insight live cell imaging mouse model novel optogenetics overexpression promoter protein aggregation proteostasis recruit repaired tau Proteins tau aggregation tau expression tau-1 trafficking

项目摘要

Protein quality control systems are essential for maintaining neuronal health, with vacuolar dependent pathways playing a primary role in these systems. The endolysosome system is a major contributor to the maintenance of the neuronal proteome, and dysfunction of this system occurs early in the pathogenesis of Alzheimer’s disease (AD) , and likely contributes to the accumulation and mislocalization of tau, which plays a key role in disease pathogenesis. Recent data provide compelling evidence that the stress responsive, multi-domain protein, Bcl-2- associated anthogene 3 (BAG3) plays a role in maintaining protein homeostasis and neuronal health. The expression of BAG3 in specific neuronal populations positively correlates with resistance to the development of tau pathology in AD. Further, our preliminary data indicate that BAG3 is an upstream regulator of vacuolar dependent pathways. The UNDERLYING PREMISE of this proposal is that in neurons, BAG3 plays a critical role in mediating vacuolar dependent pathways, and thus proteostasis and neuronal integrity. The importance of BAG3 in mediating proteostasis is illustrated by the fact that BAG3 not only plays an important role in protecting neurons from the accumulation of pathological tau species, but also likely supports synaptic structure. Nonetheless, our understanding of the mechanisms by which BAG3 regulates vacuolar dependent processes is very limited. Although previous studies have implicated BAG3 as a mediator of autophagy, we are the first to present evidence that BAG3 is a regulator of the endolysosome pathway. Further, our preliminary findings implicate BAG3 as an important modulator of endosomal sorting required for transport (ESCRT) machinery. BAG3 interacts withTBC1D10B, the primary GTPase activating protein (GAP) for Rab35, which facilitates the recruitment of the ESCRT machinery and protein clients to the endosome, as well as mediating other vacuolar dependent processes. The conceptual framework that BAG3 acts upstream of vacuolar pathways through its regulation of Rab35 activity is novel and innovative. The OVERALL HYPOTHESIS of this proposal is that the BAG3-TBC1D10B-Rab35 signaling axis regulates endosome-lysosome function and neuronal health. In the context of this overall hypothesis the specific aims of this proposal are: to test the hypotheses that: (1) the BAG3-TBC1D10B-Rab35 signaling axis regulates ESCRT and the endolysosome pathway, (2) in vivo BAG3 and Rab35 coordinate to mediate neuronal ESCRT/vacuolar processes, and contribute to the maintenance synaptic integrity, and (3) the BAG3-TBC1D10B-Rab35 axis plays a critical role in regulating the clearance of pathological tau species. These studies will be carried out using mouse models and primary neuron cultures. The IMPACT of these studies is that they will provide crucial new insights into the mechanisms by which BAG3 acts as an upstream mediator of the endolysosome systems to maintain a healthy neuron. Overall these studies represent a new, unexplored area of investigation that will increase our understanding of the factors that are essential to maintain a healthy, functional neuronal proteome.

蛋白质质量控制系统对于维持神经元健康至关重在这些系统中起主要作用。内溶性系统是维护的主要贡献者该系统的神经元蛋白质组和功能障碍发生在阿尔茨海默氏病的发病机理早期（AD），并且可能有助于TAU的积累和错误定位，这在疾病中起着关键作用发病。最近的数据提供了令人信服的证据，表明应激响应性，多域蛋白Bcl-2-- 相关的粮仓3（BAG3）在维持蛋白质稳态和神经元健康方面发挥了作用。这 BAG3在特定神经元种群中的表达与对发展的抗性 AD中的Tau病理学。此外，我们的初步数据表明BAG3是真空液的上游调节器依赖途径。该提议的基本前提是，在神经元中，Bag3扮演着关键在介导液压依赖途径的作用，从而在蛋白质上和神经元完整性。重要性 Bag3不仅在保护中起着重要作用来说明介导蛋白抑制性的Bag3 病理性tau物种的积累的神经元，但也可能支持合成结构。但是，我们对BAG3调节真空依赖性过程的机制的理解是非常有限。尽管以前的研究已经实施了Bag3作为自噬的调解人，但我们是第一个目前的证据表明BAG3是内溶血途径的调节剂。此外，我们的初步发现暗示BAG3是运输（ESCRT）机械所需的内体分类的重要调节器。 BAG3与TBC1D10B相互作用，TBC1D10B是Rab35的主要GTPase激活蛋白（GAP），它托有将ESCRT机械和蛋白质客户招募到内体，并介导其他真空依赖过程。 Bag3通过其上游的概念框架通过其上游 RAB35活性的调节是新颖而创新的。该提议的总体假设是 BAG3-TBC1D10B-RAB35信号轴调节内体 - 散糖体功能和神经元健康。在该提案的特定目的是：测试：（1） BAG3-TBC1D10B-RAB35信号轴调节ESCRT和内溶性途径，（2）体内Bag3 Rab35协调以介导神经元的ESCRT/液泡过程，并有助于维护突触完整性，（3）BAG3-TBC1D10B-RAB35轴在调节清除率中起着至关重要的作用病理性的tau物种。这些研究将使用小鼠模型和原发性神经元培养。这些研究的影响是，它们将对Bag3的机制提供至关重要的新见解。充当内溶性系统的上游介质，以维持健康的神经元。总体而言，这些研究代表一个新的，意外的投资领域，这将增加我们对因素的理解维持健康的功能性神经元蛋白质组至关重要。