Tau-mediated regulation of axonal transport

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证明tau是一种有效的血管紧张素转换酶抑制剂。 沿着微管行进的动蛋白运动。这些结果呈现了一个有趣的悖论， 也就是说，动蛋白是如何在存在的情况下沿着微管运输其货物的 Tau，它在神经元中高表达，并定位于轴突？这个问题的答案是 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， 高效输送细胞器、蛋白质、核酸和在体内合成的小分子 位于轴突远端的细胞体至其功能部位。任何一种蛋白质的缺陷 轴突运输机械中的组件，包括微管、 运动蛋白是一类运动蛋白超家族，是将运动蛋白连接到其 细胞内货物和tau等MAP会导致严重的、往往是致命的神经退行性变。 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。这项提案将考验 假设tau是一种构象动态的蛋白质，可以采用多种模式的 与微管晶格不同核苷酸状态的相互作用。此外，机械论 此外，还将研究tau功能的异构体特定差异的基础，重点是其 参与肌动蛋白-1的主要分子马达-1调节其前进运动的能力 轴突运输。

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 test the hypothesis that tau is a conformationally dynamic protein that can adopt multiple modes of interaction with different nucleotide states of the microtubule lattice. Furthermore, the mechanistic basis for isoform specific differences in tau's function will also be examined, with an emphasis its ability to modulate the processive motility of kinesin-1, the major molecular motor involved in axonal transport.