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: 9884786
• 负责人: Jihong Bai
• 金额: $ 43.6万
• 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/9884786
• 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; Mammals; Mass Spectrum Analysis; Memory; Mental disorders; Methodology; Molecular; Morphology; Movement; Mus; Myeloid-Lymphoid Leukemia Protein; 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.

神经元交流是所有认知和身体活动的基础(即，运动、感知、学习、 和内存)。高质量的沟通对维持机体的动态平衡至关重要，而干扰会导致 带来严重的后果。突触小泡(SVS)储存和释放神经递质，作为 神经递质量子的形态对应。因此，SVS的形态和功能都具有 从一个神经元传递到另一个神经元的量子信息中的重要含义。SVS的活性是 动感十足。当钙离子信号到达时，SVS与质膜融合并释放其 胞吐作用中的神经递质含量。胞吐后，SVS被合并到血浆中 膜，然后必须通过SV内吞作用被回收到新形成的囊泡中。这个SV回收是一个 已知的最协调的生物过程，同时，许多错综复杂的机制 管理回收的机构仍然不为人知。当务之急是把机理作为科学研究来把握。 认识到囊泡特性的缺陷会导致突触传递的缺陷，这是一种常见的缺陷 是各种形式的神经和精神障碍的基础。我们工作的长期目标是澄清 通过确保SVS的质量来实现有效神经元交流的基本机制。AP180、 从脑组织中分离出一种180kD的适配蛋白，已被鉴定为一种关键的突触前蛋白，并 包膜囊泡的主要成分。AP180已被牵连到人类精神疾病和 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 AP180在控制SVS的形态和蛋白质组成及其破坏原因中起着至关重要的作用 蠕虫、果蝇和小鼠的突触缺陷。以线虫线虫为模型系统，我们计划 研究并确定AP180在维持心肌细胞形态和功能完整性中的作用 在这个项目中的SVS。我们将设计和使用最先进的遗传学、细胞生物学、生物化学和 电生理学技术剖析AP180的作用。该提案有三个具体目标和 1)AP180在SV回收两步机制中的核心作用，2)耐人寻味的活动- AP180对突触动力学的依赖调节，以及3)AP180依赖的机制 控制SVS的大小。我们的假设建立在坚实的知识基础上；我们精辟的方法 有很强的前景，对SV回收有深刻的见解。在函数上获得的知识， AP180的动力学和特异性对突触活性和脑功能有广泛的影响。一起， 我们的研究有望突破现有突触传递知识的界限，拓宽 有很大潜力解开神经学的错综复杂并发明神经学解决方案的地平线 精神错乱。