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: 10385464
• 负责人: Jihong Bai
• 金额: --
• 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/10385464
• 关键词: Adaptor Signaling Protein; Address; Alzheimer' s Disease; Biochemistry; Biological Models; Biological Process; Brain; Caenorhabditis elegans; Cell membrane; Cellular biology; Clathrin-Coated Vesicles; Cognitive; Communication; Data; Defect; Drosophila genus; Electrophysiology (science); Endocytosis; Ensure; Exocytosis; Genetic; Goals; Homeostasis; Human; Knowledge; Lead; Learning; Memory; Mental disorders; Methodology; Molecular; Morphology; Movement; Mus; Nematoda; Neurodegenerative Disorders; Neurologic; Neurons; Neurotransmitters; Organism; Pathogenicity; Perception; Physical activity; Process; Property; Proteins; Public Health; Quality Control; Recycling; Regulation; Research; Role; Schizophrenia; Signal Transduction; Solid; Specificity; Synapses; Synaptic Transmission; Synaptic Vesicles; Techniques; Time; Vesicle; Work; brain tissue; design; grasp; insight; interdisciplinary approach; knowledge base; nervous system disorder; neurotransmission; neurotransmitter release; parent grant; presynaptic; quantum; synaptic function

Project Summary/Abstract (from parent grant) 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.

项目总结/摘要 (from父母补助金） 神经元通信是所有认知和身体活动的基础（即，运动，感知，学习， 记忆）。高质量的沟通对于维持机体内稳态和干扰是必不可少的 严重的后果。突触囊泡（SV）储存和释放神经递质， 神经递质量子的形态学对应物。因此，SV的形态和功能都具有 量子信息从一个神经元传递到另一个神经元的重要意义。SV的活性是 非常有活力。当Ca 2+信号到达时，SV与质膜融合并释放它们的钙离子。 通过胞吐作用释放神经递质。胞吐作用后，SV被掺入血浆 膜，然后必须收回到新形成的囊泡SV内吞作用。这个SV回收是一个 同时，许多复杂的机制， 管理回收利用的机制仍然未知。作为科学研究的一部分， 认识到囊泡性质的缺陷会导致突触传递的缺陷，这是一个常见的缺点， 是各种神经和精神疾病的基础我们工作的长期目标是阐明 通过确保SV的质量来实现有效的神经元通信的基本机制。AP180， 从脑组织中分离的180-kD衔接蛋白，已被鉴定为关键的突触前蛋白， 网格蛋白包被囊泡的主要成分。AP 180与人类精神疾病和 神经退行性疾病，包括精神分裂症和阿尔茨海默病。基因数据表明， AP 180在控制SV的形态和蛋白质组成方面起着至关重要的作用 蠕虫、果蝇和老鼠的突触缺陷。利用线虫C.作为一个模型系统，我们计划 研究并确定AP 180在维持细胞形态和功能完整性方面的作用。 SV在这个项目中。我们将设计和使用最先进的遗传学，细胞生物学，生物化学， 电生理技术来剖析AP 180的作用。该提案有三个具体目标， 地址1）在SV回收的两步机制中，AP 180的中心作用，2）有趣的活动- 突触处AP 180动力学的依赖性调节，和3）AP 180依赖性机制， 控制SV的大小。我们的假设建立在坚实的知识基础上;我们深刻的方法论 有很强的前景，以产生深入的见解SV回收。从函数中获得的知识， AP 180的动力学和特异性在突触活动和脑功能中具有广泛的分支。我们一起努力， 我们的研究有望推动目前突触传递知识的边界， 具有强大潜力的视野，可以解开神经系统的复杂性，并发明神经系统的解决方案。 紊乱