Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.
Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.
复制标题
散发性 ALS 成纤维细胞中的基因表达谱定义了疾病亚型和研究药物 EH301 的代谢效应。
DOI：
10.1093/hmg/ddac118
复制
发表时间：
2022
影响因子：
3.5
通讯作者：
Manfredi,Giovanni
中科院分区：
文献类型：
--
作者：
Fels,JasmineA;Casalena,Gabriella;Konrad,Csaba;Holmes,HollyE;Dellinger,RyanW;Manfredi,Giovanni
肌萎缩侧索硬化症（ALS）中出现了神经系统和皮肤成纤维细胞之间共有的代谢改变。最近，我们发现散发性ALS（sALS）成纤维细胞（sALS1）的一个亚组的特征是代谢谱不同于其他sALS病例（sALS2）和对照组，这表明代谢疗法可能对sALS有效。代谢调节剂烟酰胺核苷和紫檀芪（EH 301）正在临床开发中，用于治疗ALS。在这里，我们研究了sALS细胞的转录组和代谢组，以了解sALS代谢型的分子基础和EH301的影响。在基线和EH301治疗后研究代谢组学和转录组学。此外，加权基因共表达网络分析（WGCNA）被用来研究代谢和临床特征的关联。我们发现sALS1转录组与sALS2不同，并且EH301在sALS1、sALS2和对照中不同地修饰基因表达。此外，EH301对代谢应激有很强的保护作用，这种作用与代谢和抗氧化途径有关。WGCNA显示ALS功能评定量表和代谢型与细胞周期、免疫、自噬和代谢基因的基因模块相关，这些基因模块被EH301修饰。Answer ALS对来自诱导运动神经元的公开可用转录组数据的荟萃分析证实了与疾病性状相关的基因的功能关联。在机器学习模型中使用sALS成纤维细胞中差异表达的基因子集来预测疾病进展。总之，多组学分析强调了患者来源的成纤维细胞sALS中的差异代谢和转录组学特征，这转化为对研究药物EH301的差异反应。
Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.