Tau-mediated regulation of axonal transport

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，在这方面， 最近的体外运动性实验也证明了tau蛋白是一种有效的 驱动蛋白沿沿着进行性运动。这些结果提出了一个有趣的悖论， 也就是说，在存在下，驱动蛋白如何沿着沿着微管运输其货物？ tau蛋白，它在神经元中高度表达并定位于轴突？这个问题的答案 对轴突运输有重要的意义，轴突运输是神经元中的一个关键过程， 细胞器、蛋白质、核酸和小分子的有效递送， 细胞体的轴突远端区域的功能位点。任何一种蛋白质的缺陷 轴突运输机器中的组件，包括微管， 驱动蛋白超家族的马达蛋白，各种衔接分子，连接驱动蛋白，其 细胞内货物和MAP，如tau蛋白，导致严重的，往往是致命的神经退行性疾病， 疾病，包括阿尔茨海默氏症、帕金森氏症、亨廷顿氏症和ALS。这项提案将考验 假设tau蛋白是一种构象动态蛋白，可以采用多种模式， 与微管晶格的不同核苷酸状态的相互作用。此外，机械 tau蛋白功能中同种型特异性差异的基础也将被研究，重点是 调节驱动蛋白-1的进行性运动的能力，驱动蛋白-1是参与 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.