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维持神经元健康至关重要，具有液泡依赖途径