PDF(Pubmed)
Abstract：
Detrimental molecular processes in multiple sclerosis (MS) lead to the cellular accumulation of lipid peroxidation products and iron in the CNS, which represents the main driving force for ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death, with proposed roles in neurodegeneration, oligodendrocyte loss and neuroinflammation in the pathogenesis of MS. Ferroptosis-related gene expression signature and molecular markers, which could reflect MS severity and progression, are currently understudied in humans. To tackle these challenges, we have applied a curated approach to create and experimentally analyze a comprehensive panel of ferroptosis-related genes covering a wide range of biological processes associated with ferroptosis. We performed the first ferroptosis-related targeted RNAseq on PBMCs from highly distinctive MS phenotype groups: mild relapsing-remitting (RR) (n = 24) and severe secondary progressive (SP) (n = 24), along with protein detection of GPX4 and products of lipid peroxidation (MDA and 4-HNE). Out of 138 genes, 26 were differentially expressed genes (DEGs), indicating changes in both pro- and anti-ferroptotic genes, representing a molecular signature associated with MS severity. The top three DEGs, as non-core ferroptosis genes, CDKN1A, MAP1B and EGLN2, were replicated by qPCR to validate findings in independent patient groups (16 RR and 16 SP MS). Co-expression and interactions of DEGs were presented as additional valuable assets for deeper understanding of molecular mechanisms and key targets related to MS severity. Our study integrates a wide genetic signature and biochemical markers related to ferroptosis in easily obtainable PBMCs of MS patients with clinical data and disease severity, thus providing novel molecular markers which can complement disease-related changes in the brain and undergo further research as potential therapeutic targets.
摘要：
多发性硬化症（MS）中的有害分子过程导致脂质过氧化产物和铁在CNS中的细胞积累，这代表了铁中毒的主要驱动力。Ferroptosis是一种铁依赖性形式的调节细胞死亡，在神经变性中的作用，少突胶质细胞丢失和神经炎症在MS发病机制中的作用铁凋亡相关基因表达特征和分子标记,这可以反映MS的严重程度和进展，目前在人类中研究不足。为了应对这些挑战，我们已经应用了一个有组织的方法来创建和实验分析一个全面的铁凋亡相关基因组，涵盖了与铁凋亡相关的广泛的生物过程。我们对来自高度独特的MS表型组的PBMC进行了首次铁凋亡相关的靶向RNAseq：轻度复发缓解（RR）（n=24）和重度继发性进展（SP）（n=24），以及GPX4和脂质过氧化产物（MDA和4-HNE）的蛋白质检测。在138个基因中,26个差异表达基因(DEGs)，表明亲和抗铁基因的变化，代表与MS严重程度相关的分子特征。前三个DEG,作为非核心铁死亡基因，CDKN1A,通过qPCR复制MAP1B和EGLN2，以验证独立患者组（16RR和16SPMS）的发现。DEGs的共表达和相互作用作为更深入了解与MS严重程度相关的分子机制和关键靶标的额外宝贵资产。我们的研究整合了广泛的遗传特征和生化标记相关的铁死亡在MS患者的临床数据和疾病严重程度容易获得的PBMC，因此提供了新的分子标志物，可以补充大脑中与疾病相关的变化，并作为潜在的治疗靶标进行进一步的研究。
