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

• 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
• 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

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.

Corpid通过Coracle的去磷酸化促进活性区的稳定性 摘要 活动区（AZ）是位于神经末梢的特化膜隔室， 协调神经递质的释放AZ在结构上是塑性的，因为它们的数量、尺寸、 位置和强度都可以通过发展线索和神经网络来动态地修改。 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， 其功能障碍可能导致认知障碍。然而，我们对它知之甚少。 调节AZ支架动力学的分子机制。我们发现突触PP2A/PP2d 磷酸酶促进AZ在果蝇NMJ的稳定性，并且是光诱导AZ所必需的。 在成年阶段，光感受器突触的重塑和味觉学习。通过 比较蛋白质组学的方法，我们确定了Coracle（科拉，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枢蛋白，作为一种 可以介导AZ支架动力学的关键的BAD特异性底物。这项建议 解决了以下两个问题：第一，什么是在突触的Coracle的作用， 发展与稳定？第二， PP2A改变了Coracle在突触前末梢的作用？在目标1中，我们将定义一个 突触定位Cora在发育和成熟时调节AZ动力学中的新作用 突触，以及学习和记忆。在目标2中，我们将定义如何通过 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