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.

项目摘要/摘要 免疫功能障碍和突触修剪的失衡被认为是导致 神经发育障碍，如自闭症谱系障碍(ASD)和精神分裂症。最新研究 提示补体调节失调可能与此有关。神经元突触上的补体沉积 通过小胶质细胞调节突触修剪，并在大脑发育的关键窗口完善神经回路。 在炎症性和神经退行性疾病中，补体也可以异常地标记突触以移除 疾病。自我导向的补体活性通常受补体调节蛋白的抑制。 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了 补体介导的突触修剪的研究，是这项拨款的主题。我们的初步数据显示 Sez6家族(由Sez6、Sez6L和Sez6L2组成)是一种新的补体抑制剂。Sez6家族 成员在发育过程中和成年期由神经元高度表达。Sez6蛋白已经被 可调节突触数量、突触可塑性和树突形态。Sez6基因的遗传缺失 基因会导致认知受损和运动障碍。Sez6家族成员也与 自闭症、精神分裂症、智力残疾、癫痫和双相情感障碍。我们认为Sez6蛋白 通过抑制补体介导的突触调节突触数量和脑发育 由小胶质细胞进行修剪。此外，这一过程中的干扰可能会导致 神经发育障碍，如自闭症。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干扰 病人。然后将确定Sez6家族的基因敲除表型是否依赖于补体和/或 炎症环境加剧了母体免疫的激活。最后，我们将调查 Sez6蛋白胞浆尾部的神经元活性和内吞模体是否存在差异 将Sez6蛋白及其补体抑制功能置于活性突触的细胞表面 弱小和不适当的突触。这将结合特定神经元的功能强度 到突触的连接可以通过补体介导的修剪来标记和移除。这项研究 该计划将深入了解Sez6蛋白是如何防止过量的保护因子的机制 补体介导的小胶质细胞修剪可能与多种疾病的发病机制特别相关 神经发育障碍，如自闭症。