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Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis.

细胞类型特异性转录组学将neddylation鉴定为多发性硬化的新治疗靶点。

  • 影响因子:0
  • DOI:10.1093/brain/awaa421
  • 作者列表:"Kim K","Pröbstel AK","Baumann R","Dyckow J","Landefeld J","Kogl E","Madireddy L","Loudermilk R","Eggers EL","Singh S","Caillier SJ","Hauser SL","Cree BAC","UCSF MS-EPIC Team.","Schirmer L","Wilson MR","Baranzini SE
  • 发表时间:2021-03-03
Abstract

:Multiple sclerosis is an autoimmune disease of the CNS in which both genetic and environmental factors are involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbour genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in patients with multiple sclerosis are still open questions in the field. To assess cell type-specific gene expression in a large cohort of patients with multiple sclerosis, we sequenced the whole transcriptome of fluorescence-activated cell sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive patients with multiple sclerosis (n = 106) and healthy subjects (n = 22). We identified 479 differentially expressed genes in CD4+ T cells, 435 in monocytes, and 54 in CD8+ T cells. Importantly, in CD4+ T cells, we discovered upregulated transcripts from the NAE1 gene, a critical subunit of the NEDD8 activating enzyme, which activates the neddylation pathway, a post-translational modification analogous to ubiquitination. Finally, we demonstrated that inhibition of NEDD8 activating enzyme using the specific inhibitor pevonedistat (MLN4924) significantly ameliorated disease severity in murine experimental autoimmune encephalomyelitis. Our findings provide novel insights into multiple sclerosis-associated gene regulation unravelling neddylation as a crucial pathway in multiple sclerosis pathogenesis with implications for the development of tailored disease-modifying agents.

摘要

: 多发性硬化症是CNS的自身免疫性疾病,其中涉及遗传和环境因素。全基因组关联研究揭示了超过200个风险位点,其中大多数基因主要在免疫细胞中表达。然而,遗传差异是否被翻译成细胞特异性基因表达谱,以及这些在多发性硬化患者中的改变程度仍然是该领域的悬而未决的问题。为了评估一大群多发性硬化患者的细胞类型特异性基因表达,我们对初治多发性硬化患者的荧光激活细胞分选T细胞 (CD4 + 和CD8 +) 和CD14 + 单核细胞的全转录组进行了测序 (n   = 106) 和健康受试者 (n = 22)。我们在CD4 + T细胞中鉴定了479个差异表达基因,在单核细胞中鉴定了435个,在CD8 + T细胞中鉴定了54个。重要的是,在CD4 + T细胞中,我们发现了来自NAE1基因的上调转录物,NAE1基因是NEDD8活化酶的一个关键亚基,它激活neddylation通路,这是一种类似于泛素化的翻译后修饰。最后,我们证明使用特异性抑制剂pevonedistat (MLN4924) 抑制NEDD8活化酶可显著改善小鼠实验性自身免疫性脑脊髓炎的疾病严重程度。我们的研究结果为多发性硬化相关基因调控揭示neddylation作为多发性硬化发病机制中的关键通路提供了新的见解,并对定制疾病调节剂的开发产生影响。

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