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

• 批准号: 10372193
• 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
• 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/10372193
• 关键词: ASD patient; Adult; Affect; Ataxia; 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 (Brain); 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; TimeLine; 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

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.

项目总结/摘要 免疫功能障碍和突触修剪的不平衡已经被认为是导致神经元损伤的因素。 神经发育障碍，如自闭症谱系障碍（ASD）和精神分裂症。最近的研究 提示可能涉及补体失调。神经元突触上的补体沉积， 介导小胶质细胞的突触修剪并在大脑发育的关键窗口期间细化神经回路。 补体还可以异常标记突触，以在炎症和神经退行性疾病中清除。 疾病自我导向的补体活性通常由补体调节蛋白控制 在细胞膜上表达。然而，补体抑制剂的作用在很大程度上被忽视， 补体介导的突触修剪的研究，是这个补助金的主题。我们的初步数据显示 Sez 6家族（由Sez 6、Sez 6L和Sez 6L 2组成）是新型补体抑制剂。sez 6家族 成员在发育期间和成年期由神经元高度表达。SEZ 6蛋白质已经被 显示调节突触数量、突触可塑性和树突形态。Sez 6基因缺失 基因导致认知受损和运动缺陷。Sez 6家族成员也与 自闭症、精神分裂症、智力障碍、癫痫和双相情感障碍。我们认为Sez 6蛋白 通过抑制补体介导的突触，调节突触数量和大脑发育。 通过小胶质细胞修剪。此外，这一过程的中断可能有助于 神经发育障碍，如ASD。我们将研究补体调节的机制， Sez 6家族成员以及这些成员是否被先前在ASD中鉴定的错义突变破坏 患者然后将确定Sez 6家族基因敲除表型是否是补体依赖性的和/或 由母体免疫激活的炎症环境加剧。最后，我们将调查 Sez 6蛋白质胞质尾区的神经元活性和内吞基序是否与 将Sez 6蛋白及其补体抑制功能置于活性突触的细胞表面， 脆弱和不合适的突触这将结合特定神经元的功能强度， 连接到突触，可以标记和补体介导的修剪删除。本研究 该计划将提供深入了解Sez 6蛋白如何成为对抗过度免疫的保护因子的机制。 补体介导的小胶质细胞修剪，可能特别相关的发病机制， 神经发育障碍，如ASD。