Integrative systems and functional analyses reveal a role of dopaminergic signaling in myelin pathogenesis
Integrative systems and functional analyses reveal a role of dopaminergic signaling in myelin pathogenesis
复制标题
综合系统和功能分析揭示多巴胺能信号在髓磷脂发病机制中的作用
DOI：
10.1186/s12967-020-02276-1
复制
发表时间：
2020-03-02
影响因子：
7.4
通讯作者：
Xing, Lingyan
中科院分区：
文献类型：
--
作者：
Ding, Sujun;Gu, Yun;Xing, Lingyan
研究背景在中枢神经系统中，轴突周围的髓鞘是电信号传递的关键。髓鞘缺陷疾病，如多发性硬化症（MS）是破坏性的神经系统疾病，几乎没有有效的治疗方法。多巴胺能系统的功能障碍已在多种神经系统疾病中观察到。它在髓鞘发病机制中的作用，但是，是不清楚的。MethodsThis工作使用了文献策展，生物信息学，药理学和遗传操作，以及共聚焦成像技术相结合。文献检索用于建立与人类MS相关的完整基因集。生物信息学分析包括与人类遗传关联研究的途径富集和串扰分析，以及与转录组数据的基因集富集和因果关系分析。应用药理学和CRISPR/Cas9（成簇规则间隔短回文重复序列/CRISPR相关蛋白9）遗传操作来抑制斑马鱼中的多巴胺能信号传导。成像技术被用来可视化髓鞘形成在vivo.ResultsSystematic分析人类的遗传关联的研究表明，多巴胺能突触信号通路是丰富的候选基因集。转录组分析证实多发性硬化症患者多个多巴胺能基因组的表达发生了显著改变。通路串扰分析和基因组因果关系分析揭示了多巴胺能突触信号通路与多发性硬化症的其他关键通路相互作用或相关。我们还发现，多巴胺能系统的破坏导致斑马鱼髓鞘缺乏。髓鞘发病机制。这项研究可能为神经系统脱髓鞘提供一种新的分子机制。
BackgroundMyelin sheaths surrounding axons are critical for electrical signal transmission in the central nervous system (CNS). Diseases with myelin defects such as multiple sclerosis (MS) are devastating neurological conditions for which few effective treatments are available. Dysfunction of the dopaminergic system has been observed in multiple neurological disorders. Its role in myelin pathogenesis, however, is unclear.MethodsThis work used a combination of literature curation, bioinformatics, pharmacological and genetic manipulation, as well as confocal imaging techniques. Literature search was used to establish a complete set of genes which is associated with MS in humans. Bioinformatics analyses include pathway enrichment and crosstalk analyses with human genetic association studies as well as gene set enrichment and causal relationship analyses with transcriptome data. Pharmacological and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) genetic manipulation were applied to inhibit the dopaminergic signaling in zebrafish. Imaging techniques were used to visualize myelin formation in vivo.ResultsSystematic analysis of human genetic association studies revealed that the dopaminergic synapse signaling pathway is enriched in candidate gene sets. Transcriptome analysis confirmed that expression of multiple dopaminergic gene sets was significantly altered in patients with MS. Pathway crosstalk analysis and gene set causal relationship analysis reveal that the dopaminergic synapse signaling pathway interacts with or is associated with other critical pathways involved in MS. We also found that disruption of the dopaminergic system leads to myelin deficiency in zebrafish.ConclusionsDopaminergic signaling may be involved in myelin pathogenesis. This study may offer a novel molecular mechanism of demyelination in the nervous system.