Molecular Mechanisms That Control the Quality of Synaptic Vesicle Recycling

控制突触小泡回收质量的分子机制

• 批准号: 10132350
• 负责人: Jihong Bai
• 金额: $ 21.42万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132350
• 关键词: Adaptor Signaling Protein; Address; Alzheimer' s Disease; Behavior; Binding; Biochemistry; Biological Models; Biological Process; Brain; C-terminal; Caenorhabditis elegans; Cell membrane; Cellular biology; Cessation of life; Clathrin; Clathrin-Coated Vesicles; Cognitive; Communication; Data; Defect; Drosophila genus; Electron Microscopy; Electrophysiology (science); Endocytosis; Endosomes; Ensure; Equilibrium; Excision; Exocytosis; Fluorescence Recovery After Photobleaching; Foundations; Genetic; Goals; Homeostasis; Human; Impairment; Knowledge; Lead; Learning; MLL gene; Mammals; Mass Spectrum Analysis; Memory; Mental disorders; Methodology; Molecular; Morphology; Movement; Mus; N-terminal; Natural regeneration; Nematoda; Neurodegenerative Disorders; Neurologic; Neurons; Neurotransmitters; Organism; Pathogenicity; Perception; Phosphatidylinositol 4,5-Diphosphate; Physical activity; Plant Roots; Play; Process; Property; Proteins; Public Health; Quality Control; Recycling; Regulation; Research; Retrieval; Role; SNAP receptor; Schizophrenia; Shapes; Signal Transduction; Solid; Specificity; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Techniques; Time; Vesicle; Work; base; brain tissue; clathrin assembly protein AP180; design; grasp; insight; interdisciplinary approach; knowledge base; light microscopy; nervous system disorder; neurotransmission; neurotransmitter release; novel; paralogous gene; phosphatidylinositol phosphate, PtdIns(4,5)P2; premature; presynaptic; quantitative imaging; quantum; receptor; sensor; soluble NSF attachment protein; synaptic function; vesicle-associated membrane protein

Neuronal communication underpins all cognitive and physical activities (i.e., movement, perception, learning, and memory). High quality communication is essential to maintain organism homeostasis and disruptions lead to severe consequences. Synaptic vesicles (SVs) store and release neurotransmitters and serve as morphological counterparts of the neurotransmitter quanta. Thus, both morphology and function of SVs have significant implications in the quantal information transmitted from one neuron to another. The activity of SVs is highly dynamic. Upon arrival of Ca2+ signals, SVs fuse with the plasma membrane and release their neurotransmitter content through exocytosis. After exocytosis, SVs are incorporated into the plasma membrane and then must be retrieved into newly formed vesicles by SV endocytosis. This SV recycling is one of the best-orchestrated biological processes known, and at the same time, many of the intricate mechanisms that govern recycling remain unknown. It is imperative to gain a grasp of the mechanisms as scientific research recognizes that defects in vesicle property creates deficits in synaptic transmission, a common failing that underlies various forms of neurological and psychiatric disorders. The long-term goal of our work is to elucidate the fundamental mechanisms underlying effective neuronal communication by ensuring quality of SVs. AP180, a 180-kD adapter protein isolated from brain tissues, has been identified as a critical presynaptic protein and major component of clathrin-coated vesicles. AP180 has been implicated in human psychiatric and neurodegenerative disorders including schizophrenia and Alzheimer’s disease. Genetic data demonstrate that AP180 has crucial roles in controlling the morphology and protein composition of SVs and its disruption causes synaptic defects in worms, fruit flies, and mice. Using the nematode C. elegans as a model system, we plan to investigate and firmly establish the role of AP180 in maintaining both morphological and functional integrity of SVs in this project. We will design and employ state-of-the-art genetics, cell biology, biochemistry, and electrophysiological techniques to dissect the role of AP180. The proposal has three specific aims and addresses 1) the central role of AP180 in a two-step mechanism for SV recycling, 2) the intriguing activity- dependent regulation of AP180 dynamics at the synapse, and 3) the AP180-dependent mechanism that controls the size of SVs. We have built our hypotheses on solid knowledge base; our incisive methodologies have strong prospects to yield deep insights into SV recycling. The knowledge gained on the function, dynamics, and specificity of AP180 has broad ramifications in synaptic activity and brain function. Together, our studies hold promise to push boundaries of the current knowledge of synaptic transmission and broaden horizons with a strong potential to unravel the neurological intricacies and invent solutions for neurological disorders.

神经元通讯是所有认知和身体活动（即运动、感知、学习、 和记忆）。 突触小泡（SV）储存和释放神经递质并充当严重后果。 神经递质量子的形态单位因此，SV 的形态和功能都具有。 SV 的活动对从一个神经元传递到另一个神经元的定量信息具有重要意义。 高度动态的 Ca2+ 信号到达后，SV 与质膜融合并释放它们。 通过胞吐作用释放神经递质含量。胞吐作用后，SV 被纳入血浆。 膜，然后必须通过 SV 内吞作用回收到新形成的囊泡中，这种 SV 回收就是其中之一。 已知的最佳编排的生物过程，同时，许多复杂的机制 控制回收的机制仍然未知，必须通过科学研究来掌握其机制。 认识到囊泡特性的缺陷会造成突触传递的缺陷，这是一个常见的缺陷 我们工作的长期目标是阐明各种形式的神经和精神疾病。 通过确保 AP180 的质量来实现有效神经通讯的基本机制， 从脑组织中分离出的 180 kD 衔接蛋白，已被鉴定为关键的突触前蛋白，并且 AP180 是网格蛋白包被囊泡的主要成分，与人类精神疾病和疾病有关。 神经退行性疾病，包括精神分裂症和阿尔茨海默病，遗传数据表明。 AP180 在控制 SV 的形态和蛋白质组成及其破坏原因方面发挥着至关重要的作用 我们计划使用线虫、线虫和小鼠的突触缺陷。 研究并牢固确立 AP180 在维持形态和功能完整性方面的作用 我们将在这个项目中设计和采用最先进的遗传学、细胞生物学、生物化学和技术。 电生理技术剖析 AP180 的作用 该提案具有三个具体目标和 解决了 1) AP180 在 SV 回收两步机制中的核心作用，2) 有趣的活动 - 突触处 AP180 动态的依赖性调节，以及 3) AP180 依赖性机制 我们在扎实的知识基础上建立了我们的假设； 具有深入了解 SV 回收功能的前景， AP180 的动力学和特异性对突触活动和大脑功能具有广泛的影响。 我们的研究有望突破当前突触传递和拓宽知识的界限 具有揭示神经系统复杂性并发明神经系统解决方案的强大潜力的视野 失调。