REVIEW ARTICLE Differentially expressed microRNA in multiple sclerosis: A window into pathogenesis? Nellie A. Martin and Zsolt Illes Department of Neurology, Odense University Hospital and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark Keywords biomarker; cerebrospinal fluid; microRNA; multi- ple sclerosis; silencing Correspondence Zsolt Illes, MD PhD, Department of Neurology, Odense University Hospital and Institute of Clinical Research, University of Southern Denmark, SDR Boulevard 29, 5000 Odense C, Denmark. Tel: +45-6541-5332 Fax: +45 6613-8622 Email: zsolt.illes@rsyd.dk Received: 28 March 2014; revised: 22 April 2014; accepted: 23 April 2014. Abstract MicroRNA are small non-coding RNA that mediate mRNA translation repres- sion or mRNA degradation, and thereby refine protein expression levels. More than 30–60% of all genes are regulated by microRNA. Exploring dis- ease-related microRNA signatures is an emerging tool in biomarker discov- ery, and silencing has already been used in a clinical phase 2a trial. As microRNA regulate translation of more than 100 genes, they could also pro- vide a focused insight into important pathways, and offer a better under- standing of diseases with heterogeneous pathogenesis. The number of studies investigating microRNA related to multiple sclerosis has increased significantly in recent years. Differentially expressed microRNA have been identified in the whole blood, serum, plasma, cerebrospinal fluid, peripheral blood mononuclear cells, blood-derived cell subsets and brain lesions of patients with multiple sclerosis. Most studies applied a non-candidate approach of screening by microarray and validation by quantitative poly- merase chain reaction or next generation sequencing; others used a candi- date-driven approach. Despite a relatively high number of multiple sclerosis- associated microRNA, just a few could be repeatedly found, even if similar biological materials were examined. Only part of the identified microRNA has been extensively studied, and the biological function has not been explored in the majority. Some of the microRNA related to multiple sclerosis are also differentially expressed in other autoimmune diseases or autoim- mune models. In the present review, we discuss microRNA related to dis- ease compartments, activity and phenotype. We also focus on several microRNA with well-defined functions, or because of particular interest due to either validation by several independent studies or in-depth exploration of function. (Clin. Exp. Neuroimmunol. doi: 10.1111/cen3.12131, June 2014) Introduction Heterogeneity of multiple sclerosis Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system (CNS). 1 Worldwide prevalence is estimated to be 30 per 100 000, but this number is increasing. The preva- lence varies significantly and could be related to eth- nicity: in some countries with mainly Caucasian populations, it is approaching 200 per 100 000, whereas it can be as low as five per 100 000 or even lower in Asian countries. 2 In addition to the regional differences, the prevalence also changes with lati- tude. 3 The pathology of MS was originally defined by inflammation, focal demyelination in the white mat- ter and astrocytic gliosis. During recent years, this view has changed substantially, and the heteroge- neous nature of pathological processes most probably reflecting variable pathogenesis have come into focus. 4 Pathological alterations depend on their loca- tion, 5 on the stage of the disease when they arise, 6 and on the activity and stage of the demyelinated lesion. 7 An interindividual heterogeneity of active © 2014 Japanese Society for Neuroimmunology 149 Clinical and Experimental Neuroimmunology 5 (2014) 149–161 Clinical & Experimental Neuroimmunology