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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：
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
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/10583544
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 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

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.

摘要