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（由适用提供）：在学习和记忆形成期间，在称为“突触可塑性”的过程中，基于神经活动模式选择性地重组神经元之间的突触连接。这种现象的基础是合成蛋白的精确递送，例如神经递质接收器，粘合剂分子和离子通道，可改变合成强度和细胞对活性的令人兴奋的细胞。局部翻译已成为一种重要的机制，可促进蛋白质递送到树突状位置，从神经元体内长距离延伸。固体和整体膜蛋白的潜水阵列是局部合成的，包括谷氨酸受体亚基和神经素，对于某些形式的突触可塑性很重要。然而，整体膜蛋白的递送不仅需要蛋白质合成的机械，而且还需要在整个秘密细胞器完成整个秘密细胞器中才能到达细胞表面，因此它们的递送变得复杂。表征树突状秘密细胞器的研究表明，许多后胞质网（ER）细胞器（例如高尔基体复合物）在树突中稀少，其功能意义尚不清楚。因此，尚不清楚局部翻译的蛋白是否经历了树突膜附近的递送，或者是否有控制其传递的特定信号。该提议解决了以下假设：树突状早期秘书途径中突触货物的分布 在空间上定义了其传递到树突状质膜，该突触活动是关键 该过程的监管。我将通过跟踪合成蛋白从树突状ER（膜蛋白的局部合成部位）到质膜来研究这一假设，以确定其递送的范围和动力学。结果将揭示该秘密途径是否到期对贩运的空间和临时控制以指导 货物到特定的树突位置，因此选择性修改某些突触。总体而言，这些发现将为了解正常认知基本方面的秘密途径的贡献，以及扰动的秘密贩运如何导致多种疾病和疾病的认知功能障碍，包括阿尔茨海默氏病，包括阿尔茨海默氏病，发育迟缓，亨廷顿的疾病和加速疾病。