Ferroptosis-related processes gene expression and gene variants: relevance for disease severity in patients with multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) involving progressive neurodegeneration. Impairment of the ferroptosis related processes lead to iron overload, lipid peroxidation, oxidative damage and mitochondrial dysfunction, molecular mechanisms involved in various neurodegenerative diseases. Comperhensive genetic regulatin of ferroptosis as orchestrated process in MS have not been investigated in humans, yet. Recently, through FerroReg project we determined the expression pattern/signature of a comprehensive set of 138 ferroptosis-related genes and (miRNAs) in highly homogenous groups of patients with distinctive MS phenotypes, mild relapse-remitting (RR) and severe secondary progressive (SP) MS in peripheral blood mononuclear cells (PBMC), using RNAseq methodology. The panel included genes with role in lipid oxidative metabolism, antioxidant defense and iron metabolism, as well as their related main transcriptional regulators. We have established networks of all ferroptosis-related differentialy expressed genes and miRNAs with regard to disease severity. Further, we performed excessive data mining to prioritize and select single nucleotide polymorphisms (SNPs) that are potential genetic regulators of the relevant ferroptosis related genes and processes with regard to their proposed functionality using publicly available data bases, literature sources, and experimentally confirmed influence on enzyme function. Selected SNPs will be analysed in association with disease severity and with molecular components/indicators of the main ferroptosis related processes, taking into account environmental and demographic factors. Experimentally confirmed functional annotations will enable design of SNP panel of the most relevant genetic variants for regulation of ferroptosis key steps and with regard to the MS severity.