Gevezova Maria, Sbirkov Yordan, Sarafian Victoria, Plaimas Kitiporn, Suratanee Apichat, Maes Michael
Department of Medical Biology, Medical University of Plovdiv, Bulgaria.
Research Institute at MU-Plovdiv, Bulgaria.
Brain Behav Immun Health. 2023 Jun 5;30:100646. doi: 10.1016/j.bbih.2023.100646. eCollection 2023 Jul.
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.
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.
We performed network, enrichment, and annotation analyses using the differentially expressed genes, transcripts, and proteins identified in ASD patients.
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.
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.
尽管自闭症谱系障碍（ASD）研究取得了进展，且有大量的基因组、转录组和蛋白质组数据可用，但关于导致ASD的神经发育障碍的潜在途径和分子特征仍存在争议。
为了描绘这些潜在特征，我们研究了从1355例ASD患者和1110例对照的大脑及外周血单核细胞（PBMC）中获得的两个最大的基因表达荟萃分析数据集。
我们使用在ASD患者中鉴定出的差异表达基因、转录本和蛋白质进行网络、富集和注释分析。
对ASD患者脑组织和PBMC中上调和下调基因的转录因子网络分析显示了八个主要转录因子，即：BCL3、CEBPB、IRF1、IRF8、KAT2A、NELFE、RELA和TRIM28。ASD患者PBMC中上调的基因网络与激活的免疫炎症途径密切相关，包括干扰素-α信号传导以及细胞对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免疫炎症途径、细胞因子产生、Toll样受体信号传导参与其中，PI3K-Akt途径起主要作用。对下调的中枢神经系统基因的分析表明在多个水平上存在电子传递链功能障碍。网络拓扑分析显示，轴突发生、神经发生、突触传递和跨突触信号调节方面的后续异常会影响神经发育，进而导致社会行为和神经认知受损。结果提示存在针对病毒感染的防御反应。
免疫炎症途径的外周激活很可能由病毒感染诱导，可能导致中枢神经系统神经炎症和线粒体功能障碍，进而导致跨突触传递异常和大脑神经发育异常。
