Tau-mediated regulation of axonal transport

Tau 介导的轴突运输调节

基本信息

批准号：
8039973
负责人：
CHRISTOPHER L. BERGER
金额：
$ 14.92万
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：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8039973
关键词：
Acetylation Alzheimer&apos s Disease Axon Axonal Transport Binding Binding Sites Biological Assay C-terminal COS Cells Cells Defect Dendrites Distal Hippocampus (Brain)Huntington Disease Image Immunofluorescence Immunologic In Vitro Individual Kinesin Kinetics Label Life Link Maps Mediating Microtubule-Associated Proteins Microtubules Modification Molecular Motor Movement Neurodegenerative Disorders Neurons Nucleic Acids Organelles Parkinson Disease Pathway interactions Post-Translational Protein Processing Process Protein Isoforms Protein Subunits Proteins RNA Splicing Regulation Role Site Staining method Stains Surface Testing Tetrahymena Translations Trichostatin A Tubulin Tubulin Interaction Variant base cell motility cellular imaging in vivo inhibitor/antagonist interest member mutant neuronal cell body polymerization research study small molecule tau Proteins tau function tau interaction tau-microtubule interaction trafficking

项目摘要

Project Summary: 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 micro tubules 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 anyone 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. We propose two interrelated hypotheses regarding the interaction of tau and microtubules in regulating kinesin motility during axonal transport: 1.) Tau bound to different sites on microtubules have distinct functions, and only tau bound to the exterior site on polymerized microtubules inhibits kinesin motility. 2.) Specific posttranslational modifications of tubulin such as acetylation promote the binding and motility of kinesin in neuronal axons even in the presence of tau.

项目概要： 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。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。这些结果提出了一个有趣的悖论，即 - 在神经元中高度表达的 tau 存在的情况下，驱动蛋白如何沿着微管持续运输其货物并定位于轴突？这个问题的答案对于轴突运输具有重要意义，轴突运输是神经元中有效递送细胞体中合成的细胞器、蛋白质、核酸和小分子所需的关键过程。它们的功能部位位于轴突的远端区域。轴突运输机制中任何蛋白质成分的缺陷，包括微管、运动蛋白驱动蛋白超家族的成员、连接轴突的各种接头分子驱动蛋白及其细胞内货物和 tau 等 MAP 会导致严重且往往致命的神经退行性疾病，包括阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症。我们提出了关于 tau 和 tau 相互作用的两个相互关联的假设。微管在轴突运输过程中调节驱动蛋白运动： 1.) 结合到微管上不同位点的 tau 具有不同的功能，并且只有结合到聚合微管的外部位点的 tau 抑制驱动蛋白运动。 2.) 特定的翻译后即使存在 tau 蛋白，微管蛋白的修饰（例如乙酰化）也会促进神经元轴突中驱动蛋白的结合和运动。