Tau-mediated regulation of axonal transport

Tau 介导的轴突运输调节

• 批准号: 7896257
• 负责人: CHRISTOPHER L. BERGER
• 金额: $ 26.47万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 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/7896257
• 关键词: Acetylation; Alzheimer' s Disease; Axon; Axonal Transport; Binding; Defect; Distal; Huntington Disease; In Vitro; Kinesin; Link; Mediating; Microtubule-Associated Proteins; Microtubules; Molecular; Motor; Movement; Neurodegenerative Disorders; Neurons; Nucleic Acids; Organelles; Parkinson Disease; Post-Translational Protein Processing; Process; Proteins; Regulation; Role; Site; Tubulin; cell motility; inhibitor/antagonist; interest; member; neuronal cell body; public health relevance; research study; small molecule; tau Proteins; tau-1; tau-microtubule interaction

DESCRIPTION (provided by applicant): 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 intracelleualr 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 post-translational modifications of tubulin such as acetylation promote the binding and motility of kinesin in neuronal axons even in the presence of tau.

描述（由申请人提供）：Tau 是一种主要在神经元中表达的微管相关蛋白（MAP），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表明，tau 蛋白是沿着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 tau 存在的情况下，驱动蛋白如何沿着微管持续运输其货物，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轴突运输具有重要意义，轴突运输是神经元中将细胞体中合成的细胞器、蛋白质、核酸和小分子有效递送到轴突远端区域的功能位点所需的关键过程。轴突运输机制中任何一种蛋白质成分的缺陷，包括微管、运动蛋白驱动蛋白超家族的成员、将驱动蛋白与其细胞内货物连接的各种接头分子以及 tau 等 MAP，都会导致严重的和通常是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。关于tau和微管在轴突运输过程中调节驱动蛋白运动的相互作用，我们提出了两个相互关联的假设：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) 微管蛋白的特定翻译后修饰（例如乙酰化）即使在 tau 存在的情况下也能促进神经元轴突中驱动蛋白的结合和运动。