Slow axonal transport of cytosolic cargoes by dynamic-recruitment - a new traffic

项目摘要 神经元中的绝大多数蛋白质在细胞体中合成， 通过一个叫做轴突运输的过程沿着沿着轴突运输并到达突触。 蛋白质如tau和突触核蛋白的缓慢轴突运输缺陷长期以来一直是研究的热点。 与包括阿尔茨海默氏症和帕金森氏症在内的许多神经退行性疾病有关 疾病，然而，这些（和其他）细胞质的轴突运输缓慢的机制 对蛋白质的了解非常少。我们在培养的神经元中开发了一个模型系统， 直接观察胞质蛋白（包括突触核蛋白）的转运，发现 这些货物以缓慢的、依赖于马达的顺行偏移一致地移动。这 这种运动以前没有报道过，可能是一种新的运动形式。 牢房内的贩运/运输。基于这些和其他来自大脑的体内数据，我们 提出了一个新的模型，其中单个胞质蛋白单体聚集和组装 转化成多蛋白质复合物，由分子马达在神经元中携带， 我们称之为“动态聚类”。在这里，我们提出了一系列的实验来测试预测 以及由该模型产生的假设。一旦完成，这些研究将回答 关于这些蛋白质的运输的长期问题，也打开了大门 研究其在病理状态下的运输。

Project Summary The vast majority of proteins in a neuron are synthesized in the cell bodies and transported along axons and up-to synapses by a process called axonal transport. Defects in slow axonal transport of proteins such as tau and ¿-synuclein have long been implicated in many neurodegenerative diseases including Alzheimer's and Parkinson's disease, however mechanisms of slow axonal transport of these (and other) cytosolic proteins is very poorly understood. We developed a model-system in cultured neurons to directly visualize the transport of cytosolic proteins (including ¿-synuclein) and found that these cargoes move coherently with a slow, motor-dependent anterograde bias. This type of movement has not been reported before and likely represents a new form of trafficking/transport within cells. Based on these and other in-vivo data from brains, we propose a new model where individual cytosolic protein monomers cluster and assemble into multi-protein complexes that are carried in neurons by molecular motors, a process we call 'dynamic clustering'. Here we propose a series of experiments to test predictions and hypotheses generated by this model. Upon completion, these studies would answer long-standing questions about the transport of these proteins and also open the door for investigation of their transport in pathologic states.