■尽管自闭症谱系障碍(ASD)研究和庞大的基因组研究取得了进展,转录组,和可用的蛋白质组数据,关于导致ASD的神经发育障碍的通路和分子特征仍存在争议.
■为了描绘这些基础签名,我们检查了从1355例ASD患者和1110例对照的脑和外周血单个核细胞(PBMC)获得的两个最大的基因表达荟萃分析数据集.
■我们执行了网络,富集,使用差异表达的基因进行注释分析,成绩单,和ASD患者中鉴定的蛋白质。
■ASD中脑组织和PBMC中上调和下调基因的转录因子网络分析显示8个主要转录因子,即:BCL3,CEBPB,IRF1,IRF8,KAT2A,NELFE,RELA,TRIM28ASD患者PBMC中上调的基因网络与活化的免疫炎症通路密切相关,包括干扰素-α信号,和细胞对DNA修复的反应。对上调的中枢神经系统基因网络的富集分析表明参与了免疫炎症途径,细胞因子产生,Toll样受体信号,主要参与PI3K-Akt途径。对下调的CNS基因的分析表明电子传输链在多个水平上的功能障碍。网络拓扑分析表明,轴突发生过程中随之而来的畸变,神经发生,突触传递,跨突触信号的调节会影响神经发育,随后会损害社会行为和神经认知。结果表明对病毒感染的防御反应。
■免疫炎症途径的外周激活,最有可能是由病毒感染引起的,可能导致中枢神经系统神经炎症和线粒体功能障碍,导致突触传递异常,和脑神经发育。
UNASSIGNED: Despite advances in autism spectrum disorder (ASD) research and the vast genomic, transcriptomic, and proteomic data available, there are still controversies regarding the pathways and molecular signatures underlying the neurodevelopmental disorders leading to ASD.
UNASSIGNED: To delineate these underpinning signatures, we examined the two largest gene expression meta-analysis datasets obtained from the brain and peripheral blood mononuclear cells (PBMCs) of 1355 ASD patients and 1110 controls.
UNASSIGNED: We performed network, enrichment, and annotation analyses using the differentially expressed genes, transcripts, and proteins identified in ASD patients.
UNASSIGNED: Transcription factor network analyses in up- and down-regulated genes in brain tissue and PBMCs in ASD showed eight main transcription factors, namely: BCL3, CEBPB, IRF1, IRF8, KAT2A, NELFE, RELA, and TRIM28. The upregulated gene networks in PBMCs of ASD patients are strongly associated with activated immune-inflammatory pathways, including interferon-α signaling, and cellular responses to DNA repair. Enrichment analyses of the upregulated CNS gene networks indicate involvement of immune-inflammatory pathways, cytokine production, Toll-Like Receptor signalling, with a major involvement of the PI3K-Akt pathway. Analyses of the downregulated CNS genes suggest electron transport chain dysfunctions at multiple levels. Network topological analyses revealed that the consequent aberrations in axonogenesis, neurogenesis, synaptic transmission, and regulation of transsynaptic signalling affect neurodevelopment with subsequent impairments in social behaviours and neurocognition. The results suggest a defense response against viral infection.
UNASSIGNED: Peripheral activation of immune-inflammatory pathways, most likely induced by viral infections, may result in CNS neuroinflammation and mitochondrial dysfunction, leading to abnormalities in transsynaptic transmission, and brain neurodevelopment.