BAG3 regulates Rab35 and the ESCRT/endolysosome pathway

BAG3 调节 Rab35 和 ESCRT/内溶酶体途径

• 批准号: 10269305
• 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
• 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/10269305
• 关键词: Aftercare; Alzheimer' s Disease; Area; Autophagocytosis; Awareness; BCL2 gene; Binding; Client; DNA cassette; Data; Dendritic Spines; Development; Disease; Endosomes; Enterobacteria phage P1 Cre recombinase; Esters; Event; Foundations; Functional disorder; GTPase-Activating Proteins; Health; Homeostasis; Injections; Investigation; Kinetics; Leucine; LoxP-flanked allele; Lysosomes; Maintenance; Mediating; Mediator of activation protein; 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 - Cell Movement; Stress; Structure; Synapses; System; Tamoxifen; Tertiary Protein Structure; Testing; Vesicle; base; 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

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要，具有液泡依赖性途径 在这些系统中扮演重要角色。内溶体系统是维持细胞增殖的主要因素。 神经元蛋白质组，该系统的功能障碍发生在阿尔茨海默病发病的早期 (AD)，并可能导致tau的积累和错误定位，而tau在疾病中发挥着关键作用 发病机制最近的数据提供了令人信服的证据表明，应激反应，多结构域蛋白，Bcl-2- 相关的花青素3（BAG 3）在维持蛋白质稳态和神经元健康中起作用。的 BAG 3在特定神经元群体中的表达与对发展的抗性正相关， AD中的tau病理学。此外，我们的初步数据表明，BAG 3是液泡膜的上游调节因子。 依赖路径。这个提议的基本前提是，在神经元中，BAG 3起着关键的作用。 在介导空泡依赖性途径中的作用，从而蛋白质稳定和神经元完整性。的重要性 BAG 3在介导蛋白质稳态中的重要作用通过BAG 3不仅在保护蛋白质稳态中起重要作用的事实来说明。 神经元的病理性tau物质的积累，但也可能支持突触结构。 尽管如此，我们对BAG 3调节液泡依赖性过程的机制的理解仍然是非常重要的。 非常有限。虽然以前的研究已经暗示BAG 3是自噬的介导者，但我们是第一个 提出了BAG 3是内溶酶体途径的调节剂的证据。此外，我们的初步发现 暗示BAG 3是转运所需内体分选（ESCRT）机制的重要调节剂。 BAG 3与TBC 1D 10 B相互作用，TBC 1D 10 B是Rab 35的主要GTP酶激活蛋白（GAP），其促进BAG 3的表达。 ESCRT机器和蛋白质客户端的招募到内体，以及介导其他空泡 依赖过程。BAG 3通过其作用于液泡通路上游的概念框架， Rab 35活性的调节是新颖的和创新的。这一建议的总体假设是， BAG 3-TBC 1D 10 B-Rab 35信号轴调节内体-溶酶体功能和神经元健康。在 这一总体假设的背景下，这一建议的具体目标是：测试假设：（1） BAG 3-TBC 1D 10 B-Rab 35信号轴调节ESCRT和内溶酶体途径，（2）体内BAG 3 Rab 35和Rab 35协调介导神经元ESCRT/空泡过程，并有助于维持神经元的ESCRT/空泡过程。 BAG 3-TBC 1D 10 B-Rab 35轴在调节突触完整性中起关键作用， 病理性tau蛋白。这些研究将使用小鼠模型和原代神经元培养物进行。 这些研究的影响是，它们将为BAG 3 作为内溶酶体系统的上游介质以维持健康的神经元。总体而言， 代表了一个新的，未探索的调查领域，将增加我们对影响人类健康的因素的理解。 对维持健康的、功能性的神经元蛋白质组至关重要。