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

描述(申请人提供)：神经元中的绝大多数蛋白质是在细胞体中合成的，并通过一种称为轴突运输的过程沿着轴突和上至突触运输。长期以来，许多神经退行性疾病包括阿尔茨海默病和帕金森病都与tau和突触核蛋白等蛋白质轴突运输缓慢的缺陷有关，然而这些(和其他)胞浆蛋白轴突运输缓慢的机制却知之甚少。我们在培养的神经元中开发了一个模型系统来直接可视化胞浆蛋白(包括突触核蛋白)的运输，并发现这些货物以缓慢的、运动依赖的顺行偏向一致地移动。这种流动以前从未报道过，很可能代表了一种新的细胞内贩运/运输形式。基于这些和其他来自大脑的活体数据，我们提出了一个新的模型，在这个模型中，单个胞浆蛋白单体聚集并组装成多蛋白复合体，这些复合体由分子马达携带在神经元中，这一过程我们称为“动态聚集”。在这里，我们提出了一系列实验来测试由该模型产生的预测和假设。完成后，这些研究将回答长期存在的关于这些蛋白质运输的问题，并为研究它们在病理状态下的运输打开大门。

DESCRIPTION (provided by applicant): 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.