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

• 批准号: 8296187
• 负责人: Subhojit Roy
• 金额: $ 36.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/8296187
• 关键词: Actins; Acute; Address; Adult; Alzheimer' 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

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. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases like Alzheimer's and Parkinson's disease are a huge burden on our society and economy. These diseases are characterized by early deficits in synapses - the 'communication hub' of the brain; as well as impairments in axonal transport - the mechanism that that actually delivers various proteins into these synapses thereby maintaining their physiology throughout life. In pathologic states, the axonal transport of many proteins like tau and ¿-synuclein are thought to be impaired, and yet the mechanisms that move these proteins in axons and deliver them to the synapses is unknown. We have now developed new models where we can directly visualize and quantify the slow axonal transport of these pathology-related proteins in neurons and we hope that increased knowledge of the normal physiology will lead to advances in pathologic mechanisms that operate in these diseases. In the very least, these models will finally allow us to test specific disease- related hypotheses that has not been possible due to our inability to assay this transport modality.

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。 公共卫生相关性：阿尔茨海默氏症和帕金森氏症等神经退行性疾病给我们的社会和经济带来了巨大的负担。这些疾病的特征是突触的早期缺陷--大脑的“通信枢纽”；以及轴突运输的障碍--轴突运输实际上是将各种蛋白质输送到这些突触的机制，从而在一生中维持它们的生理功能。在病理状态下，许多蛋白质如tau和突触核蛋白的轴突运输被认为是受损的，但这些蛋白质在轴突中移动并将它们输送到突触的机制尚不清楚。我们现在已经开发了新的模型，我们可以直接可视化和量化这些病理相关蛋白在神经元中缓慢的轴突运输，我们希望对正常生理学的了解的增加将导致在这些疾病中起作用的病理机制的进展。至少，这些模型最终将允许我们测试特定的与疾病相关的假设，而由于我们无法分析这种运输方式，这些假设是不可能的。