Tau protein turnover and mitochondrial stress responses

Tau 蛋白周转和线粒体应激反应

• 批准号: 9761421
• 负责人: Gail V. W. Johnson
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761421
• 关键词: Acetylation; Address; Age; Age of Onset; Aging; Alzheimer' s Disease; Animal Model; Animals; Attenuated; Autophagocytosis; Behavioral; Biological; Biosensor; Brain Diseases; Caenorhabditis elegans; Cells; Characteristics; Chronic; Collaborations; Data; Disease; Disease Progression; Epitopes; Exhibits; Foundations; Future; Genetic; Genetic Models; Genomics; Health; Impairment; Intervention; Investigation; Knowledge; Link; Lysosomes; MAPT gene; Measures; Mediator of activation protein; Mitochondria; Modeling; Modification; Molecular; Nature; Neuronal Dysfunction; Neurons; Output; Oxidative Stress; Pathogenesis; Pathologic; Phenotype; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Process; Quality Control; Reporter; Resources; Role; Site; Stereotyping; Structure; Study models; System; Tauopathies; Technology; Testing; Toxic effect; Transgenic Model; Transgenic Organisms; Whole Organism; age related; age related neurodegeneration; biological adaptation to stress; early onset; genetic resource; in vivo; insight; neurotoxicity; overexpression; protein aggregate; protein degradation; response; stem; tau Proteins; tau aggregation; tau phosphorylation; tau-1; therapeutic development

Tau is a central player in the pathogenesis of numerous age-related neurodegenerative diseases, with Alzheimer 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 many of these aberrant PTMs increase tau self-association and toxicity. 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. A CRITICAL KNOWLEDGE GAP is how these modified tau species pathologically impact neuronal function. Additionally, the underlying mechanisms responsible for the increased presence of phosphorylated and acetylated forms in AD have not been fully elucidated. It has been suggested that alterations in how pathologically modified forms of tau are targeted to the autophagic machinery and degraded could be a contributing factor, as well as the fact that they may impair selective autophagy processes. Indeed, there is 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 mechanisms. The OVERALL HYPOTHESIS of this R21 proposal is that AD relevant tau modifications slow tau turnover, impair mitochondrial quality control mechanisms and thus increase the presence of less functional mitochondria with a concomitant increase in oxidative stress and neuronal dysfunction that result in an earlier onset of an aged neuron phenotype. The NOVELTY of this project stems from its use of the model organism C. elegans and its vast repertoire of genetic, transgenic and genomic resources, which has been used extensively to investigate the molecular underpinnings of AD, as well as other tauopathies. Young and older animals will be used to delineate how the presence of these pathological relevant tau species alters these processes as a function of age. The aims of this proposal are to test the hypotheses that: (1) tau acetylated at K274 and K281, tau phosphorylated at T231, or both are not as efficiently turned over as wild type tau and impair mitophagy. C. elegans single copy transgenic models and fluorescent biosensors will be used to address this hypothesis, and (2) tau acetylated at K274 and K281, tau phosphorylated at T231, or both, exacerbate toxicity through chronic mitochondrial stress responses resulting in increased oxidative stress. The relative contribution of these responses to neuronal age-dependent deficits will be further 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 neuronal health and function. They will also provide the foundation for future studies delineating the mechanisms by which specifically modified forms of tau impair neuronal processes and identifying new targets for the development of therapeutics for AD.

Tau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脑中的tau是由异常翻译后定义的 修饰(PTM)，包括增加特定表位的磷酸化和乙酰化。这个 这一提议的基本前提是，许多这些异常的PTM增加了tau的自我联系 和毒性。虽然PTMS对不溶性纤维结构的形成有影响，但数据强烈表明 可溶形式的异常修饰的tau是神经元毒性的介体。一位批评者 知识缺口在于这些修饰的tau物种如何在病理上影响神经元功能。另外， 导致磷酸化和乙酰化形式增加的潜在机制 AD尚未完全阐明。有人认为，病理改变形式的改变 Tau的目标是自噬机制并被降解可能是一个促成因素，以及 它们可能会损害选择性的自噬过程。事实上，有数据表明，过度表达 AD相关形式的tau会导致碎片化、功能障碍的线粒体水平增加，这可能是 部分原因是线粒体吞噬功能受损，以及线粒体质量控制的其他干扰 机制。这个R21建议的总体假设是AD相关的tau修饰减慢tau 周转，损害线粒体质量控制机制，从而增加功能较差的存在 线粒体伴随氧化应激和神经元功能障碍的增加，导致早期 一种老年神经元表型的发病。这个项目的新颖性来自于它对模式生物的使用 线虫及其大量的遗传、转基因和基因组资源，已被使用 广泛研究阿尔茨海默病的分子基础，以及其他变态反应。年轻的和年长的 动物将被用来描绘这些病理上相关的tau物种的存在如何改变这些 随着年龄的增长而变化。这项提议的目的是检验以下假设：(1)tau乙酰化在 K274和K281，T231处的tau磷酸化，或两者都不像野生型tau那样有效地翻转，并且 削弱了有丝分裂癖。线虫的单拷贝转基因模型和荧光生物传感器将用于 解决这一假设，以及(2)在K274和K281处乙酰化的tau，在T231处磷酸化的tau，或两者， 通过慢性线粒体应激反应加剧毒性，导致氧化应激增加。这个 这些反应对神经元年龄依赖性缺陷的相对贡献将进一步使用Unique 在蠕虫中可利用的遗传资源。这些研究的影响将是提供至关重要的新见解 病理性tau物种损害神经元健康和功能的机制。他们还将 为未来的研究提供了基础，描述了特定修饰形式的 Tau损害神经元突起，并为AD治疗的发展确定新的靶点。