A TFEB and V-ATPase-mediated lysosomal stress sensing pathway in tauopathy

tau 蛋白病中 TFEB 和 V-ATPase 介导的溶酶体应激传感途径

• 批准号: 10583544
• 负责人: Hui Zheng
• 金额: $ 52.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583544
• 关键词: Address; Adverse effects; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Astrocytes; Atlases; Autophagocytosis; Behavioral; Binding; Brain; Cell Nucleus; Communities; Cytoplasm; Data; Dependence; Disease; Exhibits; Frontotemporal Dementia; Gene Expression; Genes; Genetic Transcription; Goals; Hippocampus; Homeostasis; Human; Immune; Immune response; Immunoprecipitation; Impairment; In Vitro; Knock-in Mouse; Knockout Mice; Link; Lysosomes; Mediating; Microglia; Mus; Mutant Strains Mice; Mutate; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Nuclear; Nuclear Translocation; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiological; Post-Translational Protein Processing; Program Research Project Grants; Property; Proteome; Proteomics; Proxy; Regulation; Regulatory Pathway; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Sorting; Stress; System; Tauopathies; Technology; Testing; Transgenic Mice; Up-Regulation; Wild Type Mouse; brain health; combat; comparative; data integration; functional decline; hyperphosphorylated tau; immunoregulation; in vivo; insight; lysosomal proteins; metabolome; metabolomics; mouse model; mutant; novel; programs; promoter; response; synergism; tau Proteins; tau aggregation; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics; vacuolar H+-ATPase

Abstract Tauopathies consist of a group of diseases, including frontotemporal dementias and the most common form Alzheimer’s disease, and are characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated Tau protein and extensive neurodegeneration. Accumulating evidence has implicated impaired autophagy-lysosome pathway in neurodegenerative diseases including Alzheimer’s disease. The Transcription Factor EB (TFEB) was discovered as a master regulator of cellular clearance through coordinated expression of autophagy and lysosomal target genes. We have found that TFEB is highly efficacious in ameliorating Tau/NFT pathology and behavioral deficits in Tau transgenic mice while exhibiting no adverse effect on wild-type mice, supporting the premise that TFEB may serve as potential therapeutic target. The overarching goal of this project is to investigate a Tau-induced TFEB lysosome-to- nucleus signaling pathway regulating lysosomal homeostasis and cellular clearance in physiological and tauopathy conditions and to identify strategies to augment this pathway for enhanced cellular clearance. Specifically, through proteomics analysis of tauopathy mouse models, we will identify how Tau pathology induces unique TFEB post-translational modifications and nuclear signaling. By leveraging the powerful lysosomal purification and profiling system made available by the Program Project Grant investigators, we will test how Tau pathology alters the lysosomal proteome, metabolome, and pH, the latter is essential for lysosomal function and critically controlled by the vacuolar ATPase (V-ATPase). Accordingly, we will test the specific TFEB/V-ATPase signaling in Tau pathogenesis and downstream glia and immune response. This project is an integral component of the Program Project Grant aimed at understanding how lysosomal function is regulated through lysosome-to-nucleus signaling pathways, how these pathways are changed in aging and Alzheimer’s disease, and how to harness these regulatory pathways to promote brain health, combat age- associated functional decline, and delay neurodegenerative diseases. This project, together with the collaborative efforts of the Program Project Grant, will create a first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome for mouse cortex and hippocampus which will be made broadly available to the research community.

抽象的 tauopathies由一组疾病组成，包括额叶痴呆症和最常见的形式 阿尔茨海默氏病，其特征是细胞内神经纤维缠结（NFTS）的积累 由高磷酸化的tau蛋白和广泛的神经退行性的聚集体组成。累积 证据损害了神经退行性疾病中的自噬 - 溶酶体途径 阿尔茨海默氏病。转录因子EB（TFEB）被发现为细胞的主调节剂 通过自噬和溶酶体靶基因协调表达的清除。我们发现 TFEB在改善tau/nft病理学方面高效，行为在tau转基因小鼠中定义 虽然对野生型小鼠没有不利影响，但支持TFEB可能是潜在的前提 治疗靶标。该项目的总体目标是调查TAU引起的TFEB溶酶体至 - 细胞核信号通路通道调节溶酶体稳态和物理和细胞清除率 陶氏病的条件并确定增强该途径以增强细胞清除率的策略。 具体而言，通过蛋白质组学分析tauopathy小鼠模型，我们将确定tau病理如何 诱导独特的TFEB翻译后修饰和核信号传导。通过利用强大的 计划项目赠款调查人员提供的溶酶体纯化和分析系统，我们将 测试tau病理如何改变溶酶体蛋白质组，代谢组和pH，后者对 溶酶体功能，由真空ATPase（V-ATPase）严格控制。根据，我们将测试 tau发病机理和下游神经胶质和免疫响应中的特定TFEB/V-ATPase信号传导。这 项目是计划项目赠款的组成部分，旨在了解溶酶体功能 通过溶酶体到核信号通路进行调节，这些途径在衰老和 阿尔茨海默氏病，以及如何利用这些监管途径来促进大脑健康，战斗年龄 - 相关的功能下降和延迟神经退行性疾病。这个项目，以及 计划项目赠款的协作努力将创建一流的老化和与陶氏病相关的 小鼠皮层和海马的溶酶体蛋白质组和代谢组的溶酶体图集（地图集） 该研究社区将广泛使用。