Tau-mediated regulation of axonal transport

Tau 介导的轴突运输调节

基本信息

批准号：
8685279
负责人：
CHRISTOPHER L. BERGER
金额：
$ 36.62万
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：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685279
关键词：
Adopted Alternative Splicing Alzheimer&apos s Disease Axon Axonal Transport Behavior Binding Biological Models C-terminal Chromosomes, Human, Pair 17 Defect Disease Distal Equilibrium Event FTD with parkinsonism Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Frontotemporal Dementia Genes Genetic Engineering Goals Guanosine Triphosphate Human Huntington Disease Imaging Techniques In Vitro Kinesin Kinetics Label Laboratories Lead Link Mediating Microtubule-Associated Proteins Microtubules Modeling Molecular Molecular Conformation Molecular Motors Motor Movement N-terminal Neurodegenerative Disorders Neurons Nucleic Acids Nucleotides Organelles Paclitaxel Parkinson Disease Parkinsonian Disorders Phosphorylation Point Mutation Population Process Proline-Rich Domain Protein Dynamics Protein Isoforms Proteins Recruitment Activity Regulation Relative (related person)Role Site Solutions Stable Populations Structure Structure-Activity Relationship Surface Testing Tubulin Work axoplasm base cell motility human PTCH2 protein in vivo inhibitor/antagonist interest mathematical model member mutant neuronal cell body novel research study single molecule small molecule tau Proteins tau function tau interaction tau-1

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 test the hypothesis that tau is a conformationally dynamic protein that can adopt multiple modes of interaction with different nucleotide states of the microtubule lattice. Furthermore, the mechanistic basis for isoform specific differences in tau's function will also be examined, with an emphasis its ability to modulate the processive motility of kinesin-1, the major molecular motor involved in axonal transport.

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 是一种有效的抑制剂驱动蛋白沿着微管进行持续运动。这些结果提出了一个有趣的悖论，即 - 在存在以下物质的情况下，驱动蛋白如何沿着微管持续运输其货物？ tau，它在神经元中高度表达并定位于轴突？这个问题的答案对轴突运输具有重要意义，轴突运输是神经元中的一个关键过程。有效输送细胞器、蛋白质、核酸和合成的小分子细胞体到轴突远端区域的功能部位。任何一种蛋白质的缺陷轴突运输机制的组成部分，其中包括微管、运动蛋白的驱动蛋白超家族，将驱动蛋白与其连接的各种接头分子细胞内货物和 tau 蛋白等 MAP 会导致严重且通常致命的神经退行性病变疾病，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（ALS）。该提案将测试假设 tau 是一种构象动态蛋白，可以采用多种模式与微管晶格的不同核苷酸状态的相互作用。此外，机械 tau 功能中异构体特异性差异的基础也将被研究，重点是其调节驱动蛋白-1（参与运动的主要分子马达）的加工运动的能力轴突运输。