Tau-mediated regulation of axonal transport

描述（由申请人提供）：Tau是主要在神经元中表达的微管相关蛋白（MAP），传统上认为其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蛋白是一种有效的抑制剂的进行性驱动蛋白运动沿着微管。这些结果提出了一个有趣的悖论，即-如何能驱动蛋白proc运输其货物沿着微管在tau蛋白的存在下，这是高度表达的神经元和本地化的轴突？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，需要将细胞器、蛋白质、核酸和细胞体中合成的小分子有效地运送到轴突远端区域的功能部位。轴突运输机制中的任何一种蛋白质组分的缺陷导致严重且通常致命的神经退行性疾病，包括阿尔茨海默氏病、帕金森氏病、亨廷顿氏病和ALS，所述轴突运输机制包括微管、马达蛋白的驱动蛋白超家族的成员、将驱动蛋白连接到其细胞内货物的多种衔接分子以及MAP如tau。我们提出了两个相互关联的假设，关于tau蛋白和微管在调节驱动蛋白运动性的轴突运输过程中的相互作用：1）Tau结合到微管上的不同位点具有不同的功能，只有Tau结合到聚合微管的外部位点抑制驱动蛋白运动。2)微管蛋白的特异性翻译后修饰如乙酰化促进驱动蛋白在神经元轴突中的结合和运动性，即使在tau蛋白存在下也是如此。

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.