Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA.
Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, 1300 York Ave, New York, NY 10065, USA.
Hum Mol Genet. 2022 Oct 10;31(20):3458-3477. doi: 10.1093/hmg/ddac118.
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.
神经和皮肤成纤维细胞之间的代谢改变在肌萎缩侧索硬化症（ALS）中已经显现。最近，我们发现一组散发性 ALS（sALS）成纤维细胞（sALS1）具有与其他 sALS 病例（sALS2）和对照不同的代谢特征，这表明代谢疗法可能对 sALS 有效。代谢调节剂烟酰胺核糖和紫檀芪（EH301）正在进行治疗 ALS 的临床开发。在这里，我们研究了 sALS 细胞的转录组和代谢组，以了解 sALS 代谢表型的分子基础和 EH301 的影响。在基线和 EH301 治疗后进行了代谢组学和转录组学研究。此外，还使用加权基因共表达网络分析（WGCNA）来研究代谢和临床特征的关联。我们发现 sALS1 的转录组与 sALS2 不同，EH301 在 sALS1、sALS2 和对照中的基因表达有不同的修饰。此外，EH301 对代谢应激具有很强的保护作用，这种作用与抗炎和抗氧化途径有关。WGCNA 显示，ALS 功能评定量表和代谢表型与富含细胞周期、免疫、自噬和代谢基因的基因模块相关，这些基因模块受 EH301 调节。对 Answer ALS 诱导的运动神经元的公开转录组数据的荟萃分析证实了与疾病特征相关的基因的功能关联。在 sALS 成纤维细胞中差异表达的一组基因用于机器学习模型来预测疾病进展。总之，多组学分析突出了患者来源的成纤维细胞 sALS 中不同的代谢和转录组特征，这些特征转化为对研究药物 EH301 的不同反应。
