Regulation of Axonal Transport by Tau

Tau 对轴突运输的调节

• 批准号: 10163881
• 负责人: CHRISTOPHER L. BERGER
• 金额: $ 39.24万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163881
• 关键词: Alzheimer' s Disease; Architecture; Axon; Axonal Transport; Behavior; Binding; Biological Assay; Biological Models; C-terminal; COS-7 Cell; Cell model; Cells; Complex; Data; Defect; Dementia; Diagnosis; Diffuse; Disease; Distal; Dominant-Negative Mutation; Dynein ATPase; Economics; Equilibrium; Family member; Frontotemporal Dementia; Future; Goals; Huntington Disease; Image; Imaging Techniques; In Vitro; Individual; Kinesin; Lead; Link; MAPT gene; Mass Spectrum Analysis; Mediating; Microscopy; Microtubule-Associated Proteins; Microtubules; Modification; Molecular; Molecular Motors; Motor; Movement; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Nucleic Acids; Organelles; PC12 Cells; Parkinson Disease; Pathogenicity; Pathologic; Phagosomes; Phosphorylation; Phosphotransferases; Photobleaching; Physiological; Process; Protein Isoforms; Proteins; Publishing; Regulation; Resolution; Role; Site; Structure; Surface; System; Tail; Tauopathies; Techniques; Testing; Translations; Tubulin; Western Blotting; Work; base; cell motility; experimental study; inhibitor/antagonist; laser tweezer; member; molecular imaging; novel; novel therapeutics; protein function; reconstitution; single molecule; small molecule; tau Proteins; tau expression; tau function; tau phosphorylation

Tau is a microtubule associated protein (MAP) primarily expressed in neurons that has traditionally been thought to promote microtubule assembly and stability in the axon. However, recent in vitro motility experiments have also demonstrated that Tau is a potent inhibitor of processive kinesin movement along microtubules. These results present an interesting paradox, namely – how can kinesin processively transport its cargo along microtubules in the presence of Tau, which is highly expressed in neurons and localized to the axon? The answer to this question has important implications for axonal transport, a critical process in neurons required for the efficient delivery of organelles, proteins, nucleic acids, and small molecules synthesized in the cell body to their site of function in distal regions of the axon. Defects in any one of the protein components in the axonal transport machinery, which includes microtubules, members of the kinesin superfamily of motor proteins, a variety of adapter molecules that link kinesin to its intracellular cargo, and MAPs such as Tau, result in serious and often lethal neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and ALS. This proposal will elucidate the mechanistic basis for isoform specific differences in Tau's ability to modulate the processive motility of the major molecular motors involved in axonal transport, including kinesin-1, kinesin-2, and kinesin-3, as well as cytoplasmic dynein. Additionally, the effects of phosphorylation of Tau at physiologically-relevant and pathogenic sites on motor protein function and microtubule organization and architecture will be examined in in vitro cellular and reconstituted protein experiments using state-of- the art single molecule imaging techniques.

tau是一种微管相关蛋白（MAP），主要在神经元中表达 传统上被认为可以促进轴突中的微管组装和稳定性。 但是，最近的体外运动实验也表明tau是一个 沿微管运动的有效抑制剂的有效抑制剂。这些结果 提出一个有趣的悖论，即 - 动力素如何在过程中运输它 在Tau存在下沿着微管的货物，在神经元中高度表达 并位于轴突？这个问题的答案对 轴突运输，有效递送所需的神经元的关键过程 细胞体合成的细胞器，蛋白质，核酸和小分子 他们在轴突降低区域的功能部位。任何一种蛋白质中的缺陷 轴突传输机械中的组件，其中包括微管，成员 运动蛋白的驱动蛋白超家族，这些蛋白质是各种辅助分子 动力蛋白到其细胞内货物，以及诸如tau之类的地图，导致严重且经常致命 神经退行性疾病，包括阿尔茨海默氏症，帕金森氏症，亨廷顿和ALS。 该提案将阐明同工型特定差异的机理基础 TAU调节主要分子电动机的过程运动能力 在轴突运输中，包括驱动蛋白-1，驱动蛋白-2和驱动蛋白-3以及细胞质 动力蛋白。此外，tau在物理相关的和 运动蛋白功能和微管组织和体系结构的致病部位 将在体外细胞和重构的蛋白质实验中检查使用最新 艺术单分子成像技术。