Regulation of Axonal Transport by Tau

Tau 对轴突运输的调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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，具有传统上被认为可以促进轴突中的微管组装和稳定性。然而，最近的体外运动实验也证明 Tau 是一种沿微管进行的驱动蛋白运动的有效抑制剂。提出了一个有趣的悖论，即驱动蛋白如何不断地运输其在 Tau 存在的情况下沿着微管运输货物，Tau 在神经元中高度表达并定位于轴突？这个问题的答案对于以下方面具有重要意义：轴突运输，神经元中有效传递信息所需的关键过程细胞体内合成的细胞器、蛋白质、核酸和小分子它们的功能位点位于轴突远端区域的任何一种蛋白质的缺陷。轴突运输机制的组成部分，包括微管、成员运动蛋白的驱动蛋白超家族的一员，各种连接分子驱动蛋白及其细胞内货物和 MAP（如 Tau）会导致严重且通常致命的神经退行性疾病，包括阿尔茨海默病、帕金森病、亨廷顿舞蹈症和肌萎缩侧索硬化症。该提案将阐明同种型特异性差异的机制基础 Tau 能够调节所涉及的主要分子马达的加工运动在轴突运输中，包括驱动蛋白-1、驱动蛋白-2和驱动蛋白-3，以及细胞质此外，Tau 磷酸化的影响与生理相关。运动蛋白功能和微管组织和结构的致病位点将使用state-of-在体外细胞和重组蛋白质实验中进行检查单分子成像技术。