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：
10601125
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/10601125
关键词：
Ablation Acceleration Acetylation Address Affect Age Age of Onset Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Attenuated Auxins Behavioral Biology Biosensor Buffers CRISPR/Cas technology Caenorhabditis elegans Cells Collaborations Data Dedications Diet Disease Disease Progression Disease model Epitopes Exercise Exhibits Foundations Genes Genetic Genetic Models Genetic Transcription Health Homeostasis Impairment Intervention Knowledge Lentivirus Measures Mediator 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 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 early onset functional decline genetic resource genome resource healthy aging imaging approach insight mimetics mitochondrial dysfunction model organism mutant neuron loss neurotoxicity novel optogenetics overexpression proteostasis proteotoxicity receptor response stem tau Proteins tau aggregation tau expression tau function tau mutation tau-1 translational potential

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是许多与年龄相关的神经退行性疾病的发病机理的中心参与者，最好的例子是阿尔茨海默氏病（AD）。广告大脑的tau由异常定义翻译后修饰（PTM），包括在磷酸化和乙酰化的增加特定表位。该提案的基本前提是特定的，疾病相关的PTM 损害tau功能会对神经元健康产生负面影响。而不溶性纤维的形成结构受PTM的影响，数据强烈表明绝对修饰的tau的固体形式是神经元毒性的介体。有数据表明与广告相关形式的过表达 tau导致碎裂，功能失调的线粒体水平增加，这可能是部分归因于由于线粒体质量控制（MQC）的线粒体以及其他扰动，因此机制。但是，关键的知识差距是这些修改的tau物种如何在物理相关的水平上会影响线粒体和神经元健康。总体该提议的假设是，与AD相关的PTM的Tau通过损害MQC发挥有毒作用机制。解决线粒体应力的能力受损会增加较小的存在功能性线粒体，氧化应激和神经元功能障碍的增加。这总体结果将是更早的老年神经元表型的发作。这个项目步骤的新颖性部分原因是使用单拷贝转基因TAU模型，避免过度表达以及将年龄作为遗传模型生物中的变量包括在内。线虫C.秀丽隐杆线从遗传，转基因和基因组资源的巨大曲目中，这些资源将被利用以研究 AD的分子基础，并定义了tau ptms的精确机制折衷的线粒体功能和加速神经元衰老。我们的初步数据支持此用特定的AD与AD相关的PTM在蠕虫中作为蠕虫的方法机械感觉神经元显示出年龄依赖性神经退行性的显着增加和抑制作用压力引起的线粒体。这些和其他初步数据为研究提供了坚实的基础在此应用程序中。该提案的目的是：（1）确定AD相关的Tau PTMS的影响关于线粒体应力反应以及这如何影响神经元健康衰老，（2）测试具有AD相关PTM的TAU损害线粒体动力学和线粒体的假设，（3）解决增强MQC是否是可行的治疗途径。这些回应的相对贡献将使用蠕虫中可用的独特遗传资源来测试神经元依赖性的缺陷。这些研究的影响将是为对机制的机制提供关键的新见解病理tau物种会损害线粒体功能和神经元健康。