Molecular Analysis of Developmental Brain Disorders Associated with Synaptic Pathology

摘要 突触是大脑最丰富和最显著的特征，提供了巨大的功能。 神经回路的多样性和可塑性。这些结构非常小，小于1毫微微升， 体积，并在其功能特性显着塑料。独特的蛋白质网络集合， 在突触后结构中富集的神经元协调了神经元的发育、维持和可塑性。 突触与智力残疾、精神分裂症、自闭症和其他疾病风险相关的基因突变 发育性脑障碍（DBD）主要由编码突触蛋白的基因所支配。这些 观察结果导致假设许多DBD是突触病理学， 发展和功能。然而，尽管人类死后样本和小鼠的组织学证据表明， 尽管模型支持这一理论，但突触病理学的分子机制仍然知之甚少。 该提案将通过结合CRISPR-基因组编辑的最新进展来解决这一知识差距 与我们开发的两种高度创新的蛋白质组学方法相结合，以实现：1）发现 与DBD相关的体内突触蛋白复合物和2）这些复合物如何被破坏 不同的DBD模型。这将大大推进我们对潜在突触病变的理解， 可能与DBD突变共病的机制。揭示这些分子机制 突触病理学有望更好地了解疾病的病因和潜在的治疗方法， 接近。

ABSTRACT Synapses are the most abundant and distinguishing feature of the brain, providing enormous functional diversity and plasticity to neural circuits. These structures are incredibly small, less than 1 femtoliter in volume, and remarkably plastic in their functional properties. Unique ensembles of protein networks that are enriched within postsynaptic structures orchestrate the development, maintenance, and plasticity of synapses. Genetic mutations associated with risk for intellectual disability, schizophrenia, autism, and other developmental brain disorders (DBDs) are predominated by genes encoding synaptic proteins. These observations have led to the hypothesis that many DBDs are synaptopathologies that alter synaptic development and function. However, while histological evidence in human postmortem samples and mouse models supports this theory, the molecular mechanisms of synaptic pathology remain poorly understood. This proposal will address this gap in knowledge by combining recent advances in CRISPR-genome editing paired with two highly innovative proteomics approaches we have developed to enable: 1) the discovery of synaptic protein complexes in vivo that are associated with DBDs and 2) how these complexes are disrupted in diverse models of DBD. This will significantly advance our understanding of potential synaptopathic mechanisms that may be comorbid across DBD mutations. Uncovering these molecular mechanisms of synaptopathology can be expected to lead to better insights of disorder etiology and potential therapeutic approaches.