Molecular Mechanism of Imac-dependent axonal transport

Imac 依赖性轴突运输的分子机制

• 批准号: 8315489
• 负责人: Stephen Raiker
• 金额: $ 4.71万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315489
• 关键词: Active Biological Transport; Adult; Amyotrophic Lateral Sclerosis; Animals; Axon; Axonal Transport; Binding; Binding Proteins; Biochemistry; Biological Neural Networks; Caenorhabditis elegans; Carrier Proteins; Cell Survival; Cells; Complex; Cytoskeletal Filaments; Data; Defect; Dense Core Vesicle; Development; Disease; Drosophila genus; Embryo; Embryonic Development; Event; Failure; Family; Family member; Functional disorder; Genetic; Goals; Golgi Apparatus; Human; Huntington Disease; Kinesin; Lead; Life; Maintenance; Mediating; Messenger RNA; Microtubules; Molecular; Molecular Biology; Molecular Motors; Morphogenesis; Morphology; Motor; Mus; Muscle; Nervous system structure; Neurites; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Organelles; Organism; Parkinson Disease; Pathology; Phase; Play; Presynaptic Terminals; Process; Proteins; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Staging; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Tertiary Protein Structure; Time; cell type; developmental disease; fly; in vivo; insight; member; meter; mutant; neuronal cell body; presynaptic; research study; synaptogenesis; trafficking

DESCRIPTION (provided by applicant): The proper function of complex neural networks relies on the development and stabilization of specific synaptic connections. In both developmental and neurodegenerative disorders disruption of proper synaptic structure and function plays a central role in the pathology of the disease. Due to the specialized morphology of neurons, active transport of proteins and organelles along cytoskeletal filaments has proven to be critical not only for cell survival, axon outgrowth but also synaptogenesis. Moreover, the kinesin superfamily of molecular motors has been implicated the neurodegenerative disorders: Amyotrophic Lateral Sclerosis, Huntington disease and Parkinson's disease. In Drosophila melangastor, our lab identified the kinesin-3 family member, Imac, to be an essential motor for synaptogenesis. In imac null mutants, axons reach their proper targets but fail to form boutons, have decreased active zones and lack synaptic vesicles at the terminals. Imac is ubiquitously expressed throughout the nervous system and throughout the life of the animal suggesting a continued role for the transport of synaptic cargo after the initial stage of synaptic maturation i the embryo. Using Drosophila genetics, this proposal aims to characterize the function of Imac-dependent transport for synapse addition during larval development, to determine if active transport of synaptic cargo is required synapse maintenance. Additionally, we will perform structure function analysis and biochemistry to identify proteins that associate with Imac to regulate trafficking and facilitate cargo binding. Our long-term goal is to further our understanding of the molecular mechanisms that regulate synapse development and maintenance. PUBLIC HEALTH RELEVANCE: This project will further characterize the role of a protein that we found to be essential for axonal transport during synaptic development. In neurons, proteins produced in the cell body need to be transported down the axons for the proper assembly of synaptic connections in the nervous system. Disruption of proper synapse formation and maintenance can lead to many forms of developmental and neurodegenerative disorders.

描述（申请人提供）：复杂神经网络的正常功能依赖于特定突触连接的发展和稳定。在发育性和神经退行性疾病中，正常突触结构和功能的破坏在疾病的病理中起着核心作用。由于神经元的特殊形态，蛋白质和细胞器沿着细胞骨架细丝的主动运输已被证明不仅对细胞存活、轴突生长而且对突触发生至关重要。此外，分子马达的运动蛋白超家族还涉及神经退行性疾病：肌萎缩性侧索硬化症、亨廷顿病和帕金森病。在果蝇中，我们的实验室发现了驱动蛋白-3家族成员，Imac，是突触发生的重要马达。在imac无效突变体中，轴突到达其适当的目标，但不能形成钮扣，活性区减少，末端缺乏突触囊泡。Imac在整个神经系统和动物的整个生命中普遍表达，这表明在胚胎突触成熟的初始阶段后，Imac在突触货物运输中继续发挥作用。利用果蝇遗传学，本研究旨在描述幼虫发育过程中依赖imac转运的突触添加功能，以确定突触货物的主动转运是否需要突触维持。此外，我们将进行结构功能分析和生物化学，以确定与Imac相关的蛋白质，以调节运输和促进货物结合。我们的长期目标是进一步了解调节突触发育和维持的分子机制。