Sez6 proteins as protection factors in complement-mediated synaptic pruning

Sez6 蛋白作为补体介导的突触修剪的保护因子

基本信息

批准号：
10599087
负责人：
JENNETTA W HAMMOND
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599087
关键词：
ASD patient Adult Affect Biological Assay Bipolar Disorder Brain Cell membrane Cell surface Cells Cerebellum Complement Complement Activation Complement Inactivators Cytoplasmic Tail Data Dendrites Deposition Development Disease Environmental Risk Factor Epilepsy Excision Family Family member Future Gene Family Genes Genetic Goals Grant Hippocampus Immune Immune System Diseases Impaired cognition Infection Inflammation Inflammatory Intellectual functioning disability Knock-out Knockout Mice Mediating Microglia Missense Mutation Modeling Morphology Motor Mus Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Pathogenesis Pathway interactions Phenotype Poly I-C Process Proteins Regulation Research Role Schizophrenia Self Direction Serum Shapes Surface Symptoms Synapses Synaptic plasticity Tertiary Protein Structure Testing Therapeutic Tissues Translating Work autism spectrum disorder cognitive disability complement pathway complement system density enhancing factor family genetics fighting functional outcomes genetic regulatory protein immune activation improved in vitro Assay inflammatory milieu insight member motor deficit motor impairment motor learning neural circuit novel programs protective factors repaired synaptic pruning therapy design timeline

项目摘要

Project Summary/Abstract Immune dysfunction and imbalances in synaptic pruning have been implicated as contributing factors to neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Recent studies suggest that dysregulation of complement may be involved. Complement deposits on neuronal synapses to mediate synaptic pruning by microglia and refine neural circuits during critical windows of brain development. Complement can also aberrantly tag synapses for removal in inflammatory and neurodegenerative diseases. Self-directed complement activity is usually held in check by complement regulatory proteins expressed on cell membranes. Nevertheless, the role of complement inhibitors has been largely ignored in studies of complement-mediated synaptic pruning and is the subject of this grant. Our preliminary data shows that the Sez6 family (consisting of Sez6, Sez6L, and Sez6L2) are novel, complement inhibitors. Sez6 family members are highly expressed by neurons during development and in adulthood. Sez6 proteins have been shown to modulate synapse numbers, synaptic plasticity, and dendrite morphology. Genetic loss of Sez6 genes results in impaired cognition and motor deficits. Sez6 family members also have genetic connections to autism, schizophrenia, intellectual disability, epilepsy, and bipolar disorder. We propose that Sez6 proteins modulate synapse numbers and brain development by putting the brakes on complement-mediated synaptic pruning by microglia. Furthermore, disruptions in this process may contribute to the pathogenesis of neurodevelopmental disorders such as ASD. We will investigate mechanisms of complement regulation by Sez6 family members and whether these are disrupted by missense mutations previously identifed in ASD patients. Then will determine if Sez6 family genetic knockout phenotypes are complement-dependent and/or exacerbated by the inflammatory environment of maternal immune activation. Finally, we will investigate whether neuronal activity and the endocytic motifs within the cytoplasmic tail of Sez6 proteins differentially place Sez6 proteins and their complement inhibitory function on the cell surface of active synapses as opposed to weak and inappropriate synapses. This would couple the functional strength of specific neuronal connections to synapses that can be tagged and removed by complement-mediated pruning. This research program will provide insight into the mechanisms of how Sez6 proteins are protective factors against excessive complement-mediated pruning by microglia that may be especially relevant to the pathogenesis of various neurodevelopmental disorders such as ASD.

项目概要/摘要免疫功能障碍和突触修剪失衡被认为是导致神经发育障碍，例如自闭症谱系障碍 (ASD) 和精神分裂症。最近的研究表明可能涉及补体失调。补充神经元突触上的沉积物在大脑发育的关键窗口期介导小胶质细胞的突触修剪并细化神经回路。补体还可以异常地标记突触，以便在炎症和神经退行性疾病中去除疾病。自我导向的补体活性通常受到补体调节蛋白的控制表达于细胞膜上。然而，补体抑制剂的作用在很大程度上被忽视了。补体介导的突触修剪的研究，是本次资助的主题。我们的初步数据显示 Sez6 家族（由 Sez6、Sez6L 和 Sez6L2 组成）是新型补体抑制剂。 Sez6家族成员在发育和成年期由神经元高度表达。 Sez6 蛋白已被显示可以调节突触数量、突触可塑性和树突形态。 Sez6 基因缺失基因会导致认知受损和运动缺陷。 Sez6 家族成员也与自闭症、精神分裂症、智力障碍、癫痫症和双相情感障碍。我们建议 Sez6 蛋白通过抑制补体介导的突触来调节突触数量和大脑发育小胶质细胞的修剪。此外，这一过程的破坏可能会导致以下疾病的发病机制：神经发育障碍，例如 ASD。我们将通过以下方式研究补体调节机制 Sez6 家族成员以及这些成员是否被先前在 ASD 中发现的错义突变所破坏患者。然后将确定 Sez6 家族基因敲除表型是否依赖于补体和/或母体免疫激活的炎症环境加剧了这种情况。最后，我们将调查 Sez6 蛋白胞质尾部内的神经元活性和内吞基序是否存在差异将 Sez6 蛋白及其补体抑制功能置于活性突触的细胞表面，而不是到弱和不适当的突触。这将耦合特定神经元的功能强度与突触的连接可以通过补体介导的修剪来标记和删除。这项研究计划将深入了解 Sez6 蛋白如何成为防止过度摄入的保护因子的机制。小胶质细胞介导的补体修剪可能与各种疾病的发病机制特别相关神经发育障碍，例如 ASD。