Sushi domain proteins as synapse protective factors in brain development and aging

项目摘要/摘要 突触的形成和消除是神经组装的基本过程 大脑在发育过程中的回路。这些突起中的缺陷导致了突触密度的异常。 大脑，它被认为与许多神经发育障碍的发病机制有关。目标是 这项拟议的研究的重点是了解寿司重复蛋白X-连锁2(SRPX2)如何调节突触 大脑中的密度。我们之前已经证明，寿司重复蛋白X连锁2(SRPX2)基因编码 一种神经元表达的分泌型突触生成蛋白，可增加中枢神经系统兴奋性突触的密度。 神经细胞。寿司重复序列主要存在于已知的外围补体调节因子中。我们的 初步数据表明，SRPX2抑制大脑中补体的激活，从而减少突触 修剪和增加突触密度。为了验证这一假设，我们提出了以下目标。目标1：威慑- 我的IF SRPX2信号通过经典的补体途径来调节突触密度和消除。 目的2：确定SRPX2是否通过与C1q结合来抑制经典补体级联反应。目标3：确定是否 SRPX2在成人和老年大脑中是维持突触所必需的。我们预期这些研究将会 为大脑发育中突触消除的分子机制提供新的见解 可能导致治疗发育和退行性脑疾病的新治疗方法。

Project Summary/Abstract Synapse formation and elimination are fundamental processes that is essential for the assembly of neural circuits in the brain during development. Defects in these processes result in abnormal synaptic densities in the brain, which is believed to contribute towards the pathogenesis of many neurodevelopmental disorders. The goal of the proposed research is to understand how Sushi Repeat Protein X-linked 2 (SRPX2) regulates synapse density in the brain. We have previously shown that the sushi repeat protein X-linked 2 (SRPX2) gene codes for a neuronally-expressed secreted synaptogenic protein that increases the density of excitatory synapses in cor- tical neurons. Sushi repeats are predominantly found in known complement regulators in the periphery. Our preliminary data suggests that SRPX2 inhibits complement activation in the brain, thereby decreasing synapse pruning and increasing synapse density. To test this hypothesis, we proposed the following aims. Aim 1: Deter- mine if SRPX2 signals through the classical complement pathway to regulate synapse density and elimination. Aim 2: Determine if SRPX2 inhibits the classical complement cascade by binding to C1q. Aim 3: Determine if SRPX2 is required in the adult and aged brain for synapse maintenance. We anticipate that these studies will provide new insights into the molecular mechanisms underlying synapse elimination in the developing brain, and may lead to novel therapeutic approaches for treating developmental and degenerative brain disorders.