Wrd promotes active zone stability through dephosphorylation of Coracle

Wrd 通过 Coracle 去磷酸化促进活性区稳定性

基本信息

批准号：
10811227
负责人：
Chunlai Wu
金额：
$ 41.25万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811227
关键词：
Address Adult Affect Behavior Brain Cell Adhesion Molecules Chemosensitization Communities Cues Data Defect Development Drosophila genus Engineering Functional disorder Future Genetic Homologous Gene Impaired cognition Intellectual functioning disability Intercellular Junctions Ion Channel Learning Light Link Location Mediating Membrane Membrane Proteins Memory Modeling Modification Molecular Mutate Mutation Nerve Nervous System Neuroglia Neuromuscular Junction Neuronal Plasticity Neurons Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Photoreceptors Play Presynaptic Terminals Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Proteomics Regulation Research Role Septate Serine Signal Transduction Site Synapses Synaptic Receptors Taste Perception Testing Transgenes Work cognitive function comparative fly gain of function glycogen synthase kinase 3 beta learning ability loss of function mutant nervous system disorder neural neurotransmitter release novel postsynaptic presynaptic response scaffold synaptic function synaptogenesis treatment strategy

项目摘要

Wrd promotes active zone stability through dephosphorylation of Coracle Abstract Active zones (AZs) are specialized membrane compartments at the nerve terminal that orchestrate the release of neurotransmitters. AZs are structurally plastic as their number, size, location and strength can each be dynamically modified by developmental cues and neural activities. This form of structural neuroplasticity may play key roles in learning and memory, and its dysfunction may cause cognitive impairment. However, we know very little about the molecular mechanisms that regulate AZ scaffold dynamics. We found that synaptic PP2A/Wrd phosphatase promotes AZ stability at the Drosophila NMJs, and is required for light-induced AZ remodeling at the photoreceptor synapses and taste learning at the adult stage. Through a comparative proteomic approach, we identified Coracle (Cora, mammalian homologue is called protein 4.1), a hub protein that organizes intercellular junctions and membrane proteins, as a key Wrd-specific substrate that could mediate the AZ scaffold dynamics. This proposal addresses the following two questions: First, what are the roles of Coracle in synaptic development and stabilization? Second, how does the dephosphorylation of Coracle by Wrd/PP2A alter the action of Coracle at the presynaptic terminal? In Aim 1, we will define a novel role of synaptically localized Cora in regulating AZ dynamics at the developing and mature synapses, as well as learning and memory. In Aim 2, we will define how Wrd-mediated dephosphorylation of Cora affects Cora-mediated action in regulating synaptic stability and cognitive function.

Wrd 通过 Coracle 去磷酸化促进活性区稳定性抽象的活性区 (AZ) 是神经末梢的特殊膜区，协调神经递质的释放。 AZ 在结构上是可塑的，因为它们的数量、大小、位置和强度都可以通过发育线索和神经系统动态修改活动。这种形式的结构神经可塑性可能在学习和记忆中发挥关键作用，并且其功能障碍可能会导致认知障碍。然而，我们对此知之甚少调节 AZ 支架动力学的分子机制。我们发现突触 PP2A/Wrd 磷酸酶促进果蝇 NMJ 的 AZ 稳定性，并且是光诱导 AZ 所必需的感光器突触的重塑和成年阶段的味觉学习。通过一个通过比较蛋白质组学方法，我们鉴定出Coracle（Cora，哺乳动物同源物被称为蛋白 4.1），一种组织细胞间连接和膜蛋白的中心蛋白，作为可以介导 AZ 支架动力学的关键 Wrd 特异性底物。这个提议解决以下两个问题：第一，Coracle 在突触中的作用是什么？发展和稳定？二、Coracle如何去磷酸化 Wrd/PP2A 改变了 Coracle 在突触前末端的作用？在目标 1 中，我们将定义一个突触定位 Cora 在调节发育和成熟阶段 AZ 动态中的新作用突触，以及学习和记忆。在目标 2 中，我们将定义 Wrd 介导的方式 Cora 的去磷酸化影响 Cora 介导的调节突触稳定性的作用认知功能。