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:
  • 金额:
    $ 57.09万
  • 依托单位:
  • 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

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发病机制的核心参与者, 老年痴呆症就是最好的例子。来自AD脑的Tau定义为异常的 翻译后修饰(PTM),包括磷酸化和乙酰化的增加, 特异性表位本提案的基本前提是,特定的疾病相关PTM 损害tau功能,这对神经元健康产生负面影响。当形成不溶性的水溶性化合物时, 结构受到翻译后修饰的影响,数据强烈表明异常修饰的tau的可溶形式 神经元毒性的介质。有数据表明AD相关形式的过度表达 tau蛋白导致破碎的、功能障碍的线粒体水平增加,这可能部分是由于 由于受损的线粒体自噬,以及线粒体质量控制(MQC)的其他干扰 机制等然而,一个关键的知识差距是这些修饰的tau物种,当 存在于生理相关水平,影响线粒体和神经元健康。整体 该提议的假设是,具有AD相关PTM的tau蛋白通过损害MQC发挥毒性作用 机制等解决线粒体压力的能力受损会增加 功能性线粒体,伴随氧化应激和神经元功能障碍的增加。的 总的结果将是老化神经元表型的较早发生。这个项目的新颖之处在于 部分原因是其使用了避免过表达的单拷贝转基因tau模型,以及 将年龄作为变量包括在遗传模式生物中。线虫C.优雅的好处 从大量的遗传、转基因和基因组资源中, AD的分子基础,并确定tau蛋白PTM 损害线粒体功能并加速神经元老化。我们的初步数据支持这一点 方法作为具有tau的单拷贝表达的蠕虫,具有特异性AD相关PTM, 机械感觉神经元显示出年龄依赖性神经变性的显著增加和抑制, 压力诱导的线粒体自噬这些和其他初步数据为研究提供了坚实的基础 在这个应用中。本提案的目的是:(1)确定AD相关tau蛋白PTM的影响 线粒体应激反应以及这如何影响神经元的健康衰老,(2)为了测试线粒体应激反应, 假设具有AD相关PTM的tau会损害线粒体动力学和线粒体自噬,以及(3)To 解决增强MQC是否是一种可行的治疗途径。这些反应的相对贡献 将使用蠕虫中独特的遗传资源来测试神经元年龄依赖性缺陷。的 这些研究的影响将是提供关键的新见解的机制, 病理性tau种类损害线粒体功能和神经元健康。

项目成果

期刊论文数量(0)
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Gail V. W. Johnson其他文献

Glycogen Synthase Kinase 3β Phosphorylates Tau at Both Primed and Unprimed Sites
糖原合酶激酶 3β 在引发和未引发的位点磷酸化 Tau
Metal-catalyzed oxidation of bovine neurofilaments in vitro.
牛神经丝的体外金属催化氧化。
  • DOI:
  • 发表时间:
    1995
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    Juan C. Troncoso;Anthony C. Costello;James H. Kim;Gail V. W. Johnson
  • 通讯作者:
    Gail V. W. Johnson

Gail V. W. Johnson的其他文献

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{{ truncateString('Gail V. W. Johnson', 18)}}的其他基金

Mitochondrial dysfunction and tau pathology in Alzheimer's disease
阿尔茨海默病中的线粒体功能障碍和 tau 病理学
  • 批准号:
    10805120
  • 财政年份:
    2023
  • 资助金额:
    $ 57.09万
  • 项目类别:
Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
星形胶质细胞中转谷氨酰胺酶 2 (TG2) 介导的基因表达机制
  • 批准号:
    10293984
  • 财政年份:
    2021
  • 资助金额:
    $ 57.09万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10269305
  • 财政年份:
    2021
  • 资助金额:
    $ 57.09万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10461933
  • 财政年份:
    2021
  • 资助金额:
    $ 57.09万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10667539
  • 财政年份:
    2021
  • 资助金额:
    $ 57.09万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10374933
  • 财政年份:
    2020
  • 资助金额:
    $ 57.09万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10188394
  • 财政年份:
    2020
  • 资助金额:
    $ 57.09万
  • 项目类别:
Tau protein turnover and mitochondrial stress responses
Tau 蛋白周转和线粒体应激反应
  • 批准号:
    9761421
  • 财政年份:
    2018
  • 资助金额:
    $ 57.09万
  • 项目类别:
The degradation of tau by selective autophagy
选择性自噬降解 tau
  • 批准号:
    9395850
  • 财政年份:
    2017
  • 资助金额:
    $ 57.09万
  • 项目类别:
The degradation of tau by selective autophagy
选择性自噬降解 tau
  • 批准号:
    9918995
  • 财政年份:
    2017
  • 资助金额:
    $ 57.09万
  • 项目类别:

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