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

通过动态募集缓慢轴突运输细胞质货物 - 一种新的交通

基本信息

批准号：
8507831
负责人：
Subhojit Roy
金额：
$ 4.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507831
关键词：
Actins Acute Address Adult Alzheimer&apos s Disease Axon Axonal Transport Biochemistry Biological Assay Biological Models Brain Carrier Proteins Cell physiology Cells Co-Immunoprecipitations Collaborations Communication Complex Coupled Cytoskeletal Proteins Data Defect Disease Distal Dynein ATPase Employee Strikes Figs - dietary Health Homeostasis Image Impairment Individual Investigation Kinesin Kinetics Knowledge Lead Life Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Microfilaments Minor Modality Modeling Molecular Molecular Chaperones Molecular Motors Motion Motor Movement Mutation Neurodegenerative Disorders Neurons Parkinson Disease Pathologic Pathology Peptides Physiologic pulse Physiology Population Process Protein Biosynthesis Proteins Proteome Proteomics Radiolabeled Regulatory Element Reporting Resolution Scaffolding Protein Series Societies Structure Synapses Technology Testing Vesicle alpha synuclein base design fast axonal transport in vivo insight member monomer neuronal cell body neuronal circuitry neuronal transport particle photoactivation presynaptic protein complex protein transport radiotracer research study slow axonal transport small hairpin RNA synuclein tau Proteins trafficking

项目摘要

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.

描述（由应用程序提供）：神经元中的绝大多数蛋白质是在细胞体中合成的，并通过称为轴突运输的过程沿轴突和最新突触进行运输。在包括阿尔茨海默氏病和帕金森氏病在内的许多神经退行性疾病中，蛋白质（如Tau和®）慢速轴突运输的缺陷已被实现，但是这些（和其他）胞质蛋白的慢速轴突转运的机制是非常熟悉的。我们在培养的神经元中开发了一个模型系统，以直接可视化胞质蛋白的转运（包括�-Synuclein），并发现这些货物以缓慢的运动依赖性依赖性的偏置相干地移动。这种类型的运动以前尚未报告，并且可能代表了细胞内的一种新形式的运输/运输形式。基于这些大脑的这些和其他体内数据，我们提出了一个新模型，其中单个胞质蛋白蛋白质单体簇并将其组装成多蛋白质复合物，这些复合物通过分子电动机在神经元中携带，这一过程称为“动态聚类”。在这里，我们提出了一系列实验，以测试该模型产生的预测和假设。完成后，这些研究将回答有关这些蛋白质运输的长期问题，并为其在病理状态的运输投资打开了大门。