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: 9270091
• 负责人: Aaron Bowen
• 金额: $ 4.4万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270091
• 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; Huntington Disease; Impaired cognition; Integral Membrane Protein; Ion Channel; Kinetics; Lead; Learning; Ligands; Location; Mediator of activation protein; Membrane; Membrane Proteins; Memory; Microscopy; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitter Receptor; Organelles; Pathway interactions; Pharmacology; 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; experimental study; membrane synthesis; neural patterning; neuroligin 1; neuronal cell body; neuropsychiatric disorder; protein transport; public health relevance; receptor; 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神经活动模式选择性地重组，这一过程称为“突触可塑性”。这种现象的背后是突触蛋白的精确、受调节的传递，例如神经递质受体、粘附分子和离子通道，它们可以改变突触强度和细胞对活动的兴奋性。局部翻译已成为一种重要机制，有助于将蛋白质递送至远离神经元胞体的树突位置。多种可溶性和整合膜蛋白是局部合成的，包括谷氨酸受体亚基和神经连接蛋白，它们对于某些形式的突触可塑性很重要。然而，整合膜蛋白的递送很复杂，因为它们不仅需要蛋白质合成的机制，而且还需要通过整个分泌细胞器来到达细胞表面。表征树突分泌细胞器的研究表明，许多后内质网（ER）细胞器，例如高尔基复合体，在树突内很少见，其功能意义尚不清楚。因此，尚不清楚局部翻译的蛋白质是否会传递到树突膜的附近区域，或者是否存在控制其传递的特定信号。该提案提出了这样的假设：突触货物在树突早期分泌途径中的分布 空间上定义了其向树突质膜的传递，突触活动是关键 对这一过程的监管。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）传输到质膜的过程来研究这一假设，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贩运发挥空间和时间控制，以指导 将货物运送到特定的树突位置，从而选择性地修改某些突触。总体而言，这些发现将为了解分泌途径对正常认知基本方面的贡献，以及分泌物运输扰乱如何导致多种疾病和障碍（包括阿尔茨海默病、发育迟缓、亨廷顿病和自闭症）的认知功能障碍奠定基础。