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，它提供了巨大的功能 神经回路的多样性和可塑性。这些结构非常小，不到1飞升 体积，而且在功能特性上具有显著的可塑性。独一无二的蛋白质网络集合 丰富的突触后结构协调着突触的发育、维持和可塑性 突触。基因突变与智力残疾、精神分裂症、自闭症和其他疾病的风险相关 发育性脑疾病(DBD)主要由编码突触蛋白的基因主导。这些 观察结果导致假设，许多DBD是改变突触的突触病理 发展和功能。然而，虽然在人类尸检样本和小鼠身上发现的组织学证据 模型支持这一理论，但突触病理的分子机制仍知之甚少。 这项提议将通过结合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，可以实现：1)发现 体内与DBD相关的突触蛋白复合体以及2)这些复合体是如何被破坏的 在不同型号的DBD中。这将极大地促进我们对潜在的突触病变的理解 可能在DBD突变中并存的机制。揭示了这些分子机制 突触病理学有望更好地洞察疾病的病因和潜在的治疗方法 接近了。

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.