Dynamic Control of Local Synaptic-Membrane Protein Composition by the Dendritic Secretory Pathway

树突分泌途径动态控制局部突触膜蛋白组成

• 批准号: 9084272
• 负责人: Aaron Bowen
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9084272
• 关键词: AMPA Receptors; Address; Alzheimer' s Disease; Area; Autistic Disorder; Cell Adhesion Molecules; Cell membrane; Cell surface; Characteristics; Cognition; Complement; Data; Dendrites; Development; Developmental Delay Disorders; Diffusion; Dimensions; Disease; Endoplasmic Reticulum; Foundations; Future; Glutamate Receptor; Glutamates; Golgi Apparatus; Health; Huntington Disease; Impaired cognition; Integral Membrane Protein; Ion Channel; Kinetics; Lead; Learning; Ligands; Location; Mediator of activation protein; Membrane; Membrane Protein Traffic; Membrane Proteins; Memory; Microscopy; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitter Receptor; Organelles; Pathway interactions; Plasma; Play; Process; Property; Protein Biosynthesis; Proteins; Resolution; Role; Schizophrenia; Signal Transduction; Site; Spatial Distribution; Stimulus; Surface; Synapses; Synaptic Membranes; Synaptic plasticity; System; Testing; Translating; Translations; Variant; addiction; autism spectrum disorder; base; cognitive function; experience; neural patterning; neuroligin 1; neuronal cell body; neuropsychiatric disorder; protein transport; receptor coupling; research study; response; small molecule; targeted delivery; trafficking

 DESCRIPTION (provided by applicant): During learning and memory formation, synaptic connections between neurons are selectively reorganized based on patterns of neural activity in a process called "synaptic plasticity". Underlying this phenomenon is the precise, regulated delivery of synaptic proteins, such as neurotransmitter receptors, adhesion molecules and ion channels that modify synaptic strength and cellular excitability in response to activity. Local translation has emerged as an important mechanism that facilitates protein delivery to dendritic locations long-distances from the neuronal soma. A diverse array of soluble and integral-membrane proteins are locally synthesized, including glutamate receptor subunits and neuroligins that are important for certain forms of synaptic plasticity. However, the delivery of integral-membrane proteins is complicated by the fact that they require not just the machinery for protein synthesis, but also trafficking through the entire complement of secretory organelles to reach the cell surface. Studies characterizing the dendritic secretory organelles have revealed that many of the post-endoplasmic reticulum (ER) organelles, such as Golgi Complex, are scarce within the dendrite and their functional significance unclear. Consequently, it is unknown whether locally translated proteins undergo delivery to nearby areas of the dendritic membrane, or if there are specific signals that control their delivery. This proposal addresses the hypothesis that the distribution of synaptic cargo within the dendritic early secretory pathway spatially defines its delivery to the dendritic plasma membrane and that synaptic activity is a key regulatory of this process. I will investigate thhis hypothesis by tracking synaptic proteins as they traffic from the dendritic ER (the site of local synthesis for membrane proteins) to the plasma membrane to determine the range and kinetics of their delivery. The results will reveal whether the secretory pathway exerts spatial and temporal control of trafficking in order to direct cargo to specific dendritic locations, thus selectively modifying certain synapses. Overall, the findings will provide a foundation to understand the contribution of the secretory pathway to fundamental aspects of normal cognition, as well as how perturbed secretory trafficking may lead to cognitive dysfunction in a wide variety of diseases and disorders, including Alzheimer's disease, developmental delay, Huntington's disease, and autistic disorders.

 描述（由申请人提供）：在学习和记忆形成过程中，神经元之间的突触连接根据称为“突触可塑性”的过程中的神经活动模式进行选择性重组，这种现象的基础是突触蛋白的精确、受调节的传递。神经递质受体、粘附分子和离子通道可改变突触强度和细胞对活动的兴奋性，局部翻译已成为促进蛋白质递送的重要机制。树突位置距神经元胞体很远，可以局部合成多种可溶性整合膜蛋白，包括对某些形式的突触可塑性很重要的谷氨酸受体亚基和神经连接蛋白。复杂的事实是它们不仅需要蛋白质合成机制，还需要通过整个分泌细胞器到达细胞表面的研究表征树突分泌。细胞器显示，许多后内质网（ER）蛋白，例如高尔基复合体，在树突内很少见，其功能意义尚不清楚，目前尚不清楚是否局部翻译到传递膜的附近区域。或者是否存在控制其传递的特定信号。该提议提出了突触货物在树突早期分泌途径内分布的假设。 空间上定义了其向树突质膜的传递，突触活动是关键 我将通过跟踪突触蛋白从树突内质网（膜蛋白的局部合成位点）运输到质膜来研究这一假设，以确定其传递的范围和动力学，结果将揭示是否如此。分泌途径对贩运施加空间和时间控制，以指导 总体而言，这些发现将为理解分泌途径对正常认知的基本方面的贡献以及分泌性运输的干扰如何导致广泛的认知功能障碍奠定基础。各种疾病和病症，包括阿尔茨海默氏病、发育迟缓、亨廷顿舞蹈病和自闭症。