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发挥着核心作用，阿尔茨海默病 (AD) 就是最好的例子，AD 大脑中的 Tau 蛋白被定义为异常。翻译后修饰 (PTM)，包括磷酸化和乙酰化的增加该提案的基本前提是特定的、与疾病相关的 PTM。损害 tau 蛋白功能，对神经元健康产生负面影响，同时形成不溶性纤维。结构受到 PTM 的影响，数据强烈表明异常修饰的 tau 的可溶形式有数据表明 AD 相关形式的过度表达。 tau 导致碎片化、功能失调的线粒体水平增加，这可能部分是由于由于线粒体自噬受损以及线粒体质量控制 (MQC) 的其他扰动然而，一个关键的知识差距是这些修饰的 tau 物种何时发生。存在于生理相关水平，影响线粒体和神经元的整体健康。该提案的假设是，具有 AD 相关 PTM 的 tau 通过损害 MQC 发挥毒性作用解决线粒体应激的能力受损会增加较少的存在。功能性线粒体，伴随着氧化应激和神经元功能障碍的增加。总体结果将是老化神经元表型的早期出现，该项目的新颖性源于此。部分原因在于它使用了避免过度表达的单拷贝转基因 tau 模型，以及将年龄作为一个变量纳入遗传模型生物体中，线虫受益。来自大量遗传、转基因和基因组资源，这些资源将被用来研究 AD 的分子基础并定义 tau PTM 的精确机制我们的初步数据支持这一点。方法作为具有 tau 单拷贝表达的蠕虫，具有特定的 AD 相关 PTM 机械感觉神经元表现出年龄依赖性神经变性的显着增加和抑制这些和其他初步数据为研究提供了坚实的基础。在本申请中，该提案的目的是：（1）确定 AD 相关 tau PTM 的影响。关于线粒体应激反应及其如何影响神经元的健康衰老，(2) 测试假设 tau 蛋白与 AD 相关的 PTM 会损害线粒体动力学和线粒体自噬，以及 (3) 解决增强QC是否是一种可行的治疗途径这些反应的相对贡献。将利用线虫中独特的遗传资源来测试与年龄相关的神经缺陷。这些研究的影响将是为机制提供重要的新见解病理性 tau 蛋白会损害线粒体功能和神经元健康。