Synaptic Organizers: Dynamic Regulation of Trans-synaptic Bridges

突触组织者：跨突触桥的动态调节

• 批准号: 9910228
• 负责人: Gabrielle Rudenko
• 金额: $ 51.1万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910228
• 关键词: Address; Adhesives; Architecture; Astrocytes; Behavioral; Binding; Biochemical; Biophysics; Central Nervous System Diseases; Code; Communication; Development; Disease; Elements; Family; Foundations; Funding; Genetic; Goals; Health; Image; Inhibitory Synapse; Lesion; Ligands; Maintenance; Mediating; Membrane; Mental Retardation; Methodology; Modeling; Molds; Molecular; Neuronal Plasticity; Neurons; Pathogenesis; Pathology; Pharmaceutical Preparations; Play; Postsynaptic Membrane; Process; Proteins; RNA Splicing; Regulation; Role; Schizophrenia; Structure; Synapses; Synaptic Cleft; Techniques; Therapeutic; Work; autism spectrum disorder; base; electron tomography; extracellular; genetic regulatory protein; hevin; innovation; nervous system disorder; neural circuit; neuroligin 1; neuropsychiatric disorder; novel; particle; presynaptic; recruit; severe mental illness; structural biology; synaptic function; synaptogenesis; targeted treatment; three dimensional structure; virtual

The synaptic organizers, α-neurexins, form macromolecular bridges with their post-synaptic partners that span the synaptic cleft (‘trans-synaptic bridges’); together they play a crucial role in mediating synaptic connections and communication between neurons. α-Neurexins and their partners are implicated in neurological disorders including autism spectrum disorder, schizophrenia and mental retardation. α-Neurexin trans-synaptic bridges have traditionally been considered static. However, there is accumulating evidence that they are in fact dynamically regulated! Dynamic regulation of α-neurexin trans- synaptic bridges is important, because it means that the synapse-promoting role of α-neurexins is tunable and can be increased or decreased at a particular synapse. Three very different mechanisms have recently been revealed that control the trans-synaptic bridges between α-neurexins and their partners: 1) competing decoys, 2) proteins secreted by astrocytes, and 3) allosteric modulation of α-neurexin binding partners. However, it is not known on a molecular level how these mechanisms work. It is essential to determine the molecular bases that underlie these regulatory mechanisms, because they not only control the synapse-promoting activity of α-neurexins, but they also involve protein interactions that could be targeted to manipulate specific synaptic connectivities and exploited therapeutically. In this proposal, we will determine the molecular bases of three mechanisms that control the formation of α-neurexin trans-synaptic bridges. We hypothesize that these different molecular mechanisms exploit unique elements in the 3D structure of α-neurexins and their partners to generate platforms that permit dynamic regulation. We will use structural, biophysical and biochemical techniques to elucidate mechanisms involving 1) competing synaptic organizers, 2) astrocytic factors, and 3) allosteric modulation. Collectively, our results will reveal on a molecular level how regulatory mechanisms mold α-neurexin trans-synaptic bridges impacting synapse development and synaptic communication. This proposal is significant because genetic lesions in α-neurexins and their partners are involved in the pathogenesis of severe neurological disorders, so mechanisms regulating their interactions and functions, control their contribution to disease as well. This work will also set the stage for developing mechanism-based, focused therapies to address specific CNS disorders. This proposal is conceptually innovative because it will help establish the emerging paradigm shift that trans- synaptic bridges formed by synaptic organizers, like α-neurexins and their partners, are in fact subject to intense regulation and their ability to stabilize synaptic function is rendered tunable by other interacting proteins. This proposal is also technically innovative because it involves single particle electron tomography for which we are actively developing methodologies to image synapse organizing molecules.

突触组织者α-系素蛋白与他们的后突触伴侣形成大分子桥 跨跨突触裂（“反式突触桥”）；他们在一起在中介突触中起着至关重要的作用 神经元之间的连接和沟通。 α-系素及其伴侣在 神经系统疾病，包括自闭症谱系障碍，精神分裂症和智力低下。 传统上，α-系突触素突触桥被认为是静态的。但是，有 积累证据表明他们实际上是在动态调节的！ α-系菌素反式的动态调节 突触桥很重要，因为这意味着α-系素蛋白的突触促进作用是可调的，并且 在特定的突触时可以增加或减少。最近有三种截然不同的机制 揭示了控制α-热毒素及其伴侣之间的反射突触桥：1）竞争的诱饵， 2）由星形胶质细胞分泌的蛋白质，以及3）α-纽苏蛋白结合伴侣的变构调节。但是，是 这些机制在分子层面上未知。确定分子碱基至关重要 这是这些调节机制的基础，因为它们不仅控制着 α-系菌素，但它们也涉及蛋白质相互作用，可以针对操纵特定的突触 连接并热探索。 在此提案中，我们将确定控制形成的三种机制的分子碱基 α-系突触素突触桥。我们假设这些不同的分子机制利用了独特的 α-热毒素及其伴侣的3D结构中的元素，以生成允许动态的平台 规定。我们将使用结构，生物物理和生化技术来阐明涉及的机制 1）竞争突触组织者，2）星形细胞因子和3）变构调节。总体而言，我们的结果 将在分子水平上揭示调节机制如何塑造α-纽苏蛋白反式突触桥的影响 突触发展和突触通信。该提议很重要，因为遗传病变 α-系菌素及其伴侣参与严重神经系统疾病的发病机理，因此机制 调节其相互作用和功能，也控制其对疾病的贡献。这项工作也将设定 开发基于机制的，重点疗法以解决特定中枢神经系统疾病的阶段。这 提案在概念上具有创新性，因为它将有助于建立新兴的范式转变 合成组织者形成的突触桥，例如α-纽龙及其伴侣，实际上受到 强烈的调节及其稳定突触功能的能力可以通过其他相互作用来调节 蛋白质。该建议在技术上也是创新的，因为它涉及单粒子电子断层扫描 为此，我们正在积极开发图像突触组织分子的方法。