Regulation of Axonal Transport by Tau

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，最近的体外运动性实验也表明，Tau是一种具有生物学活性的蛋白质。 沿沿着微管进行性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-如何驱动蛋白proc运输其 货物沿着微管在Tau的存在下，这是高度表达的神经元 并定位在轴突上这个问题的答案对以下方面具有重要意义： 轴突运输是神经元中有效传递神经元所需的关键过程， 细胞器、蛋白质、核酸和小分子在细胞体内合成， 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 轴突运输机制中的组件，包括微管， 作为马达蛋白驱动蛋白超家族的一员， 驱动蛋白与其细胞内货物，以及MAP如Tau，导致严重的，通常是致命的 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ALS。 这一建议将阐明的机制基础异构体的具体差异， Tau调节主要分子马达进行性运动的能力 在轴突运输中，包括驱动蛋白-1、驱动蛋白-2和驱动蛋白-3，以及细胞质 动力蛋白此外，Tau在生理学相关的和生理学相关的水平上的磷酸化的影响也是显著的。 运动蛋白功能和微管组织和结构的致病位点 将在体外细胞和重组蛋白质实验中进行检查， 本领域的单分子成像技术。

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.