Tau-mediated regulation of axonal transport

项目总结： Tau是一种微管相关蛋白(MAP)，主要在神经元中表达，传统上被认为促进轴突中微管的组装和稳定性。然而，最近的体外运动实验也证明了tau是一种 有效地抑制沿着微管进行的动蛋白运动。这些结果提出了一个有趣的悖论，即在神经元中高度表达tau的情况下，kinesin如何沿着微管运输其货物。 并定位在轴突上？这个问题的答案对轴突运输具有重要的意义，轴突运输是神经元有效地将细胞器、蛋白质、核酸和在细胞体中合成的小分子运送到 它们的功能部位在轴突的远端区域。轴突运输机制中的任何蛋白质成分都有缺陷，包括微管，运动蛋白超家族的成员，各种连接的适配分子 到其细胞内货物的动蛋白，以及tau等映射，会导致严重的、往往是致命的神经退行性疾病，包括阿尔茨海默氏症、帕金森氏症、亨廷顿氏症和肌萎缩侧索硬化症。我们就tau和tau的相互作用提出了两个相互关联的假说。 微管在轴突运输过程中对动蛋白运动的调节：1。微管上不同部位结合的tau具有不同的功能，只有与聚合微管外部部位结合的tau才能抑制肌动蛋白的运动。2.)具体的翻译后 微管蛋白的修饰，如乙酰化，即使在tau存在的情况下，也能促进运动蛋白在神经元轴突中的结合和运动。

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.