BAG3 regulates Rab35 and the ESCRT/endolysosome pathway

BAG3 调节 Rab35 和 ESCRT/内溶酶体途径

• 批准号: 10461933
• 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/10461933
• 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 在这些系统中发挥着主要作用。内溶酶体系统是维持 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机制的早期 (AD)，并且可能导致 tau 蛋白的积累和错误定位，而 tau 蛋白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，表明应激反应性多结构域蛋白 Bcl-2- 相关 anthogene 3 (BAG3) 在维持蛋白质稳态和神经元健康中发挥作用。这 BAG3 在特定神经元群体中的表达与对 AD 中的 tau 病理学。此外，我们的初步数据表明 BAG3 是液泡的上游调节因子。 依赖途径。该提议的基本前提是，在神经元中，BAG3 起着至关重要的作用。 在介导液泡依赖性途径中发挥作用，从而介导蛋白质稳态和神经元完整性。重要性 BAG3 不仅在保护蛋白质中发挥重要作用，这一事实说明了 BAG3 在介导蛋白质稳态中的作用。 神经元来自病理性tau蛋白的积累，但也可能支持突触结构。 尽管如此，我们对 BAG3 调节液泡依赖过程的机制的理解是 非常有限。尽管之前的研究表明 BAG3 是自噬的介质，但我们是第一个 有证据表明 BAG3 是内溶酶体途径的调节剂。此外，我们的初步发现 表明 BAG3 是运输 (ESCRT) 机制所需的内体分选的重要调节剂。 BAG3 与 Rab35 的主要 GTP 酶激活蛋白 (GAP) TBC1D10B 相互作用，从而促进 将 ESCRT 机制和蛋白质客户招募到内体，以及介导其他液泡 依赖进程。 BAG3 通过其作用于液泡通路上游的概念框架 Rab35 活性的调控是新颖且创新的。该提案的总体假设是 BAG3-TBC1D10B-Rab35 信号轴调节内体-溶酶体功能和神经元健康。在 在这个总体假设的背景下，该提案的具体目标是：检验以下假设：(1) BAG3-TBC1D10B-Rab35信号轴调节ESCRT和内溶酶体途径，（2）体内BAG3 和 Rab35 协调介导神经元 ESCRT/液泡过程，并有助于维持 突触完整性，(3) BAG3-TBC1D10B-Rab35 轴在调节突触清除中发挥关键作用 病理性 tau 物种。这些研究将使用小鼠模型和原代神经元培养物进行。 这些研究的影响在于，它们将为 BAG3 的机制提供重要的新见解。 作为内溶酶体系统的上游介质，维持健康的神经元。总的来说这些研究 代表了一个新的、未经探索的研究领域，它将增加我们对影响因素的理解 对于维持健康、功能性的神经元蛋白质组至关重要。