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）：在学习和记忆形成期间，神经元之间的突触连接基于称为“突触可塑性”的过程中的神经活动模式而选择性地重组。这种现象的基础是突触蛋白质的精确、受调节的递送，例如神经递质受体、粘附分子和离子通道，它们响应于活动而改变突触强度和细胞兴奋性。局部翻译已成为一种重要的机制，有助于蛋白质递送到远离神经元索马的树突位置。各种各样的可溶性和完整的膜蛋白是局部合成的，包括谷氨酸受体亚基和神经连接素，它们对某些形式的突触可塑性很重要。然而，整合膜蛋白的传递是复杂的，因为它们不仅需要蛋白质合成的机器，而且还需要通过整个分泌细胞器的补充来到达细胞表面。树突分泌细胞器的研究表明，许多内质网（ER）后的细胞器，如高尔基复合体，在树突内是稀缺的，其功能意义尚不清楚。因此，目前还不清楚局部翻译的蛋白质是否会传递到树突状细胞膜的附近区域，或者是否有特定的信号控制它们的传递。这一建议提出了一个假设，即突触货物的分布在树突早期分泌途径 在空间上定义了其向树枝状质膜的递送，突触活动是关键 监管这个过程。我将通过跟踪突触蛋白从树突状ER（膜蛋白的局部合成部位）到质膜的交通来研究这一假设，以确定其传递的范围和动力学。结果将揭示分泌途径是否对运输施加空间和时间控制，以指导 货物到特定的树突位置，从而选择性地修改某些突触。总的来说，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，以及干扰分泌贩运如何导致各种疾病和障碍中的认知功能障碍提供基础，包括阿尔茨海默病，发育迟缓，亨廷顿病和自闭症。