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: 10397995
• 负责人: Gabrielle Rudenko
• 金额: $ 51.14万
• 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 2023-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397995
• 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; 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-neurexins与其突触后伙伴形成大分子桥， 跨越突触间隙（“跨突触桥”）;它们一起在介导突触传递中起着至关重要的作用。 神经元之间的连接和通信。α-Neurexins和它们的伴侣与 神经障碍，包括自闭症谱系障碍、精神分裂症和精神发育迟滞。 α-神经肽跨突触桥传统上被认为是静态的。不过有 积累证据证明它们实际上是动态调节的！α-neurexin反式- 突触桥很重要，因为这意味着α-neurexins的突触促进作用是可调节的， 可以在特定的突触处增加或减少。最近，三种截然不同的机制 揭示了控制α-neurexins和它们的伴侣之间的跨突触桥梁：1）竞争诱饵， 2)由星形胶质细胞分泌的蛋白，和3）α-neurexin结合配偶体的变构调节。但据 在分子水平上不知道这些机制是如何工作的。必须确定分子基础 这些调节机制的基础，因为它们不仅控制突触促进活动， α-神经毒素，但它们也涉及蛋白质相互作用，可以靶向操纵特定的突触 联系并在治疗上加以利用。 在这个建议中，我们将确定控制形成的三种机制的分子基础。 α-neurexin跨突触桥。我们假设这些不同的分子机制利用了独特的 α-neurexins及其伙伴的3D结构中的元素，以生成允许动态 调控我们将使用结构，生物物理和生物化学技术来阐明机制， 1)竞争性突触组织者，2）星形胶质细胞因子，和3）变构调节。总的来说，我们的结果 将在分子水平上揭示调控机制如何塑造α-neurexin跨突触桥梁， 突触发育和突触通讯。这一建议是重要的，因为遗传病变， α-neurexins及其伴侣参与严重神经系统疾病的发病机制，因此， 调节它们的相互作用和功能，也控制它们对疾病的贡献。这项工作也将 开发基于机制的重点治疗以解决特定CNS疾病的阶段。这 该提案在概念上具有创新性，因为它将有助于建立新的范式转变， 由突触组织者形成的突触桥，如α-neurexins及其伴侣，实际上受到 强烈的调节和它们稳定突触功能的能力被其他相互作用的 proteins.这一提议在技术上也具有创新性，因为它涉及单粒子电子断层成像 为此我们正在积极开发方法来成像突触组织分子。