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    2019-07-30


    Conflict of interest
    Transparency document
    Introduction Multiple Sclerosis (MS) is an autoimmune disease characterized by complex genetic features and pathology that translate into clinical heterogeneity [1]. During multiple sclerosis, axonal destruction and neuronal loss occur early, and the most common prescribed medication to treat MS is interferon-β (IFN-β). It is becoming increasingly evident that microRNAs are associated with the development and progression of MS disease too [2], [3]; however, little is known about how they contribute to pathogenesis and transcriptome changes in MS. MicroRNAs are pivotal post-transcriptional gene regulation elements of 20–30 nucleotide length, which regulate negatively the gene expression by binding to complementary mRNAs [4]. MicroRNA is involved in tumors, leukemia, neurodegenerative ([5], [6]) and immuno-systems diseases by affecting the expression of multiple genes [7], [8], [9], [10]. Recently [6], [11], we found that the expression of a specific miRNA, hsa-mir-26a-5p (miR-26a), increased during INF-β treatment in the blood of responder relapsing-remitting MS Solasodine (RRMS) patients. Intriguingly, functional annotations of mir-26a potential targets revealed that a subset of the transcripts are implicated in Glutamate Receptor Signaling pathway, i.e. DLG4, GRIN3A and SLC1A1 (also known as EAAC1 or EAAT3) [11]. Glutamate metabolism is altered in neurodegenerative diseases as MS; in fact, under pathological conditions, an excess of glutamate in the synaptic space can trigger a toxic cascade; in this scenario, glutamate transporters are essential to prevent excitotoxicity by determining the levels of extracellular glutamate [12], [13]. Moreover, IFN-β has been shown to be neuroprotective against the toxicity induced by activated microglia, suppressing the production of glutamate [14], [15]. These studies point to a role of glutamate transporters in MS as a component of regulatory response of glial Solasodine to toxic levels of glutamate in the CNS during inflammation and neurodegeneration. Therefore, DLG4, GRIN3 and SLC1A1 were experimentally verified as miR-26a targets by a validation test based on luciferase reporter constructs transfected in an oligodendroglial cell line, used as model to study immune-mediated injury of oligodendrocytes in relation to multiple sclerosis. In that system, miR-26a was able to silence the SLC1A1 expression. Then, the study was extended to blood platelets from RRMS patients, revealing a converse expression profile of miR-26a and its target. Moreover, this regulatory circuit appears to be sensitive to INF-β treatment.
    Materials and methods
    Results
    Discussion Multiple sclerosis is a chronic degenerative disorder of the central nervous system characterized by demyelination, T lymphocyte infiltration, loss of oligodendrocyte and neuronal damage. INF-β is now widely used to treat the relapsing-remitting MS patients, even if its precise mechanism of action has not been fully elucidated. miRNAs and the related biogenesis machinery are widely recognized as regulators in the development and pathologies of the central nervous system (CNS) [24], [25], [26], [27]. A growing body of evidence suggests a role of miRNAs in MS; in particular, the dysregulated miRNAs have been shown to be associated with the pathogenesis of MS [2]. Recently, in an effort to determine the non-coding RNA associated with MS patients' response to INF-β, we found that miR-26a expression was significantly higher in the INF-β treated MS patients leukocytes [6], [11]. MiR-26a has been demonstrated to play a role in the central nervous system, in fact it is mainly expressed in neural tissue. miR-26a is important in neuronal development and morphogenesis [28], is a physiological regulator of mammalian axon regeneration in vivo and exactly affects the maintenance, but not induction, of synaptic plasticity and different stages of spine enlargement [29]. Moreover, miR-26a has been found dysregulated in several central nervous system diseases as multiple sclerosis [6], [11], [30].