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

基本信息

批准号：
10413975
负责人：
Hui Zheng
金额：
$ 51.31万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2021-06-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10413975
关键词：
Address Adverse effects Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos 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 (Brain)Homeostasis Human Immune Immune response Impairment In Vitro Knock-in Mouse Knockout Mice Link Lysosomes Mediating Microglia Mus 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 Stress System Tauopathies Technology Testing Transgenic Mice Up-Regulation Wild Type Mouse activating transcription factor base brain health combat comparative data integration functional decline hyperphosphorylated tau immunoregulation in vivo insight lysosomal proteins metabolome metabolomics mouse model mutant novel programs promoter protein metabolite response synergism tau Proteins tau aggregation therapeutic target transcription factor transcriptome sequencing transcriptomics vacuolar H+-ATPase

项目摘要

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 Tau蛋白病由一组疾病组成，包括额颞叶痴呆和最常见的形式阿尔茨海默病，其特征是细胞内神经原纤维缠结（NFT）的积累由过度磷酸化的 Tau 蛋白聚集体和广泛的神经变性组成。有证据表明神经退行性疾病中自噬-溶酶体途径受损，包括转录因子 EB (TFEB) 被发现是细胞的主要调节因子。我们发现，通过自噬和溶酶体靶基因的协调表达来清除。 TFEB 在改善 Tau 转基因小鼠的 Tau/NFT 病理和行为缺陷方面非常有效同时对野生型小鼠没有不良影响，支持 TFEB 可能作为潜在的假设该项目的总体目标是研究 Tau 诱导的 TFEB 溶酶体。生理和细胞核信号通路调节溶酶体稳态和细胞清除 tau蛋白病状况并确定增强该途径以增强细胞清除的策略。具体来说，通过对 tau 蛋白病小鼠模型进行蛋白质组学分析，我们将确定 Tau 蛋白病理学如何利用强大的功能诱导独特的 TFEB 翻译后修饰和核信号传导。溶酶体纯化和分析系统由计划项目资助研究人员提供，我们将测试 Tau 病理学如何改变溶酶体蛋白质组、代谢组和 pH 值，后者对于溶酶体功能并由液泡 ATP 酶（V-ATP 酶）严格控制。因此，我们将测试 Tau 发病机制和下游神经胶质细胞和免疫反应中的特异性 TFEB/V-ATPase 信号传导。该项目是该计划项目拨款的一个组成部分，旨在了解溶酶体的功能通过溶酶体到细胞核的信号传导途径进行调节，这些途径在衰老过程中如何变化以及阿尔茨海默病，以及如何利用这些调节途径来促进大脑健康、对抗衰老—— 相关的功能衰退，并延缓神经退行性疾病。计划项目拨款的共同努力，将创建一流的衰老和 Tau 病相关药物小鼠皮质和海马溶酶体蛋白质组和代谢组的溶酶体图谱 (ATLas) 它将广泛提供给研究界。