MICRORNA-125A-3P NEGATIVELY REGULATES OLIGODENDROGLIAL MATURATION AND RE-MYELINATION: MOLECULAR MECHANISMS AND CLINICAL IMPLICATIONS

Multiple sclerosis (MS) is a chronic immune-mediated de-myelinating disease of the central nervous system in which immune system attacks myelin, a substance produced by mature oligodendrocytes that normally surrounds and protects axons, leading to abnormal impulses transmission (Wu et al., 2011). During their maturation oligodendroglial precursors cells (OPCs) follow a very precise differentiation program, finely orchestrated by transcription factors, epigenetic factors and microRNAs, a class of small non-coding RNAs involved in post-transcriptional regulation (He and Lu, 2013). Any alterations in this program can potentially contribute to dysregulated myelination, impaired re-myelination and neurodegenerative conditions, as it happens in multiple sclerosis. Based on these considerations, the aim of this study was to investigate the potential role of miR-125a-3p, a brain enriched miRNA, in the regulation of OPC maturation and to assess whether its alteration can contribute to MS pathogenesis or re-myelination failure. First, our gene ontology based study showed that several of its predicted target mRNAs are involved in glial cell differentiation, myelination, axon ensheathment and oligodendrocyte differentiation, suggesting that miR-125a-3p may have a primary role in the regulation of these processes. Then, we characterized its expression pattern in the CNS, showing that it is expressed in oligodendroglial cells throughout brain development and is progressively up-regulated during OPC in vitro differentiation. We also found that the over-expression of this miRNA impairs, whereas its silencing promotes oligodendrocyte maturation in vitro, likely acting on different targets at multiple levels of the process. Interestingly, we observed an up-regulation of miR-125a-3p in two different mouse models of toxic demyelination, induced by cuprizone or lysolecithin administration, suggesting that it may represent a hallmark of de-myelination. Furthermore, the over-expression of miR-125a-3p in the white matter of mice following lysolecithin-induced demyelination maintained oligodendrocytes in the NG2-positive precursor stage, in line with the hypothesis of a delay in both their maturation and the subsequent re-myelination process. To identify new mechanisms altered by miR-125a-3p during OPC maturation, we performed a transcriptomic analysis after its over-expression in OPCs, showing that miR-125a-3p can modulate different pathways and processes, such as Wnt-signaling and expression of ECM and adhesion molecules. Globally, our data suggest that miR-125a-3p could represent a new negative regulator of re-myelination and that an antago-miRNA specific for this miRNA may help to foster oligodendrocyte maturation in diseases characterized by impaired myelin repair. The potential importance of miR-125a-3p in MS was also confirmed by the finding that it is up-regulated in the CSF of MS patients in the active phase of the disease, suggesting that it could represent a potential biomarker for the diagnosis or prognosis of different MS phases.