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Tau Post-Translational Modifications and Mitochondrial Quality Control

Tau 翻译后修饰和线粒体质量控制

基本信息

批准号：
10188394
负责人：
Gail V. W. Johnson
金额：
$ 57.09万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10188394
关键词：
Ablation Acetylation Address Affect Age Age of Onset Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Animal Model Attenuated Auxins Behavioral Biology Biosensor Buffers CRISPR/Cas technology Caenorhabditis elegans Cells Collaborations Data Disease Disease Progression Disease model Epitopes Exhibits Foundations Genes Genetic Genetic Models Genetic Transcription Genomics Health Homeostasis Impairment Intervention Knowledge Lentivirus Measures Mediator of activation protein Metabolic Mitochondria Modeling Molecular Mus Mutation Nematoda Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Organelles Output Oxidative Stress Pathogenesis Pathologic Pathway interactions Phenotype Phosphorylation Physiological Play Post-Translational Protein Processing Process Proteins Quality Control Resources Role Severities Signal Pathway Signal Transduction Site Stress Structure System Tauopathies Testing Therapeutic Time Toxic effect Transgenic Model Transgenic Organisms Translating Ubiquitin age related age related neurodegeneration biological adaptation to stress comparative diet and exercise early onset functional decline genetic resource healthy aging imaging approach insight mitochondrial dysfunction mutant neuron loss neurotoxicity novel optogenetics overexpression proteostasis proteotoxicity receptor response stem tau Proteins tau aggregation tau expression tau function tau mutation tau phosphorylation

项目摘要

Tau is a central player in the pathogenesis of numerous age-related neurodegenerative diseases, with Alzheimer’s disease (AD) being the best example. Tau from AD brain is defined by aberrant posttranslational modifications (PTMs), including increases in phosphorylation and acetylation at specific epitopes. The UNDERLYING PREMISE of this proposal is that specific, disease relevant PTMs impair tau function which negatively impacts neuronal health. While the formation of insoluble fibrillary structures is influenced by PTMs, data strongly indicate that soluble forms of abnormally modified tau are the mediators of neuronal toxicity. There are data indicating that overexpression of AD-relevant forms of tau results in increased levels of fragmented, dysfunctional mitochondria, which may be due to in part due to impaired mitophagy, as well as other perturbations of mitochondrial quality control (MQC) mechanisms. However, a CRITICAL KNOWLEDGE GAP is how these modified tau species, when present at physiologically relevant levels, influence mitochondrial and neuronal health. The OVERALL HYPOTHESIS of this proposal is that tau with AD-relevant PTMs exerts toxic effects through impairing MQC mechanisms. An impaired ability to resolve mitochondrial stress would increase the presence of less functional mitochondria with a concomitant increase in oxidative stress and neuronal dysfunction. The overall result would be an earlier onset of an aged neuron phenotype. The NOVELTY of this project stems in part from its use of single-copy transgenic tau models that avoid overexpression, as well as the inclusion of age as a variable in a genetic model organism. The nematode C. elegans benefits from a vast repertoire of genetic, transgenic and genomic resources that will be leveraged to investigate the molecular underpinnings of AD and to define the precise mechanism through which tau PTMs compromise mitochondrial function and accelerate neuronal aging. Our preliminary data support this approach as worms with single copy expression of tau with specific AD-relevant PTMs in mechanosensory neurons show a significant increase in age-dependent neurodegeneration and a suppression of stress-induced mitophagy. These and other preliminary data provide a strong foundation for the studies in this application. The aims of this proposal are: (1) To determine the impact of AD relevant tau PTMs on mitochondrial stress responses and how this influences healthy aging of neurons, (2) To test the hypothesis that tau with AD relevant PTMs impairs mitochondrial dynamics and mitophagy, and (3) To address whether enhancing MQC is a viable therapeutic avenue. The relative contribution of these responses to neuronal age-dependent deficits will be tested using unique genetic resources available in worms. The IMPACT of these studies will be to provide crucial new insights into the mechanisms by which pathological tau species compromise mitochondrial function and neuronal health.

Tau蛋白在许多与年龄相关的神经退行性疾病的发病机制中起着核心作用，