Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology

Abstract

Significance Dysregulation of microRNAs (miRNAs), a type of small noncoding RNAs (sncRNAs), has frequently been associated with multiple sclerosis (MS). However, most studies have focused on peripheral blood, and few investigated other classes of sncRNAs. To address this, we analyzed all classes of sncRNAs in matching peripheral blood mononuclear cells, plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from MS patients and controls. We demonstrate widespread alterations of small nuclear (snRNA)–derived RNAs, small nucleolar-derived RNAs (sdRNAs), transfer RNA–derived fragments, and miRNAs, particularly in CSF cells. The striking contrast between the periphery and central nervous system and between relapse and remission phases of disease highlights the importance of sncRNA-mediated mechanisms in MS, in particular alternative splicing and mRNA translation. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). Small non-coding RNAs (sncRNAs) and, in particular, microRNAs (miRNAs) have frequently been associated with MS. Here, we performed a comprehensive analysis of all classes of sncRNAs in matching samples of peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from relapsing-remitting (RRMS, n = 12 in relapse and n = 11 in remission) patients, secondary progressive (SPMS, n = 6) MS patients, and noninflammatory and inflammatory neurological disease controls (NINDC, n = 11; INDC, n = 5). We show widespread changes in miRNAs and sncRNA-derived fragments of small nuclear, nucleolar, and transfer RNAs. In CSF cells, 133 out of 133 and 115 out of 117 differentially expressed sncRNAs were increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65 out of 67 differentially expressed PBMC sncRNAs were decreased in RRMS compared to NINDC. The striking contrast between the periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation, and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the CNS target organ.