BACKGROUND Myelin 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. METHODS This 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. RESULTS Systematic 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. CONCLUSIONS Dopaminergic signaling may be involved in myelin pathogenesis. This study may offer a novel molecular mechanism of demyelination in the nervous system.

中文翻译：

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综合系统和功能分析揭示了多巴胺能信号在髓磷脂发病机制中的作用。


背景技术围绕轴突的髓鞘对于中枢神经系统(CNS)中的电信号传输至关重要。多发性硬化症 (MS) 等髓磷脂缺陷性疾病是一种毁灭性的神经系统疾病，目前几乎没有有效的治疗方法。在多种神经系统疾病中观察到多巴胺能系统功能障碍。然而，其在髓磷脂发病机制中的作用尚不清楚。方法 这项工作结合了文献整理、生物信息学、药理学和基因操作以及共焦成像技术。通过文献检索建立了一套与人类多发性硬化症相关的完整基因。生物信息学分析包括人类遗传关联研究的通路富集和串扰分析，以及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的多巴胺能信号传导。使用成像技术来可视化体内髓磷脂的形成。结果人类遗传关联研究的系统分析表明，多巴胺能突触信号通路在候选基因集中丰富。转录组分析证实，多巴胺能基因组的表达在多发性硬化症患者中显着改变。通路串扰分析和基因集因果关系分析表明，多巴胺能突触信号通路与 MS 涉及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会导致斑马鱼髓磷脂缺乏。 结论 多巴胺能信号传导可能参与髓鞘质的发病机制。这项研究可能提供神经系统脱髓鞘的新分子机制。