Regulation of Axonal Transport by Tau

Tau是一种微管相关蛋白(MAP)，主要在神经元表达，具有 传统上认为可以促进微管在轴突中的组装和稳定性。 然而，最近的体外运动实验也表明，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--运动蛋白是如何进行运输的 在神经元中高表达Tau的情况下沿微管运输的货物 并定位在轴突上？这个问题的答案对以下方面具有重要影响 轴突运输，神经元中的一个关键过程，需要有效地传递 细胞器、蛋白质、核酸和在细胞体中合成的小分子 它们的功能部位在轴突的远端区域。任何一种蛋白质的缺陷 轴突运输机械中的部件，包括微管、部件 在马达蛋白的运动蛋白超家族中，各种连接的接头分子 到其细胞内货物的动蛋白，以及Tau等MAP，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、帕金森症、亨廷顿氏症和肌萎缩侧索硬化症。 这一建议将阐明异构体特异性差异的机制基础。 Tau调节主要分子马达运动的能力 在轴突运输中，包括Kinesin-1、Kinesin-2和Kinesin-3以及胞浆 动力蛋白。此外，Tau的磷酸化对生理相关和 运动蛋白功能和微管组织与结构的致病部位 将在体外细胞和重组蛋白质实验中使用状态- ART单分子成像技术。

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 elucidate the mechanistic basis for isoform specific differences in Tau's ability to modulate the processive motility of the major molecular motors involved in axonal transport, including kinesin-1, kinesin-2, and kinesin-3, as well as cytoplasmic dynein. Additionally, the effects of phosphorylation of Tau at physiologically-relevant and pathogenic sites on motor protein function and microtubule organization and architecture will be examined in in vitro cellular and reconstituted protein experiments using state-of- the art single molecule imaging techniques.