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: 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
• 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

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中的失衡已被认为是导致因素 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 表明补体的失调可能涉及。补充神经元突触的沉积物 在脑发育的关键窗户期间，小胶质细胞和精炼神经回路介导突触修剪。 补体还可以异常地标记突触，以在炎症和神经退行性中去除 疾病。自我指导的补体活动通常通过补体调节蛋白来检查 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略了 补充介导的突触修剪的研究是该赠款的主题。我们的初步数据显示 SEZ6家族（由SEZ6，SEZ6L和SEZ6L2组成）是新颖的，补体抑制剂。 SEZ6家庭 成员在发育期间和成年期间由神经元高度表达。 SEZ6蛋白已经 显示以调节突触数，突触可塑性和树突形态。 SEZ6的遗传丧失 基因导致认知和运动缺陷受损。 SEZ6家庭成员还与 自闭症，精神分裂症，智力障碍，癫痫和躁郁症。我们建议SEZ6蛋白 通过将制动器放在补体介导的突触中，调节突触数字和大脑发育 小胶质细胞修剪。此外，此过程中的破坏可能有助于 神经发育障碍，例如ASD。我们将通过 SEZ6家族成员以及这些是否被以前在ASD中识别的错义突变所破坏 患者。然后将确定SEZ6家族遗传基因敲除表型是否依赖于补体和/或 孕产妇免疫激活的炎症环境加剧。最后，我们将调查 神经元活性和SEZ6蛋白细胞质尾部内的内吞基序是否有差异 将SEZ6蛋白及其补体抑制功能放在活性突触的细胞表面上 弱和不适当的突触。这将使特定神经元的功能强度结合 可以通过补体介导的修剪来标记和删除突触的连接。这项研究 计划将洞悉SEZ6蛋白如何成为防护因素的机制 小胶质细胞补体介导的修剪可能与各种发病机理特别相关 神经发育障碍，例如ASD。