Table 2.

Similarities between MS and MAPK^ERK pathway associated microRNA

Parameter	Association	References
miRNA-21	MicroRNA-21 is upregulated in CSF, and also found in brain white matter lesions in patients with MS Sprouty2 (SPRY2), as a critical negative regulator of MAPKERK signaling, is a target of miRNA-21. Consequently, MAPKERK signaling pathway activation is upregulated as a consequence of SPRY2 due to higher expression of this microRNA	[36–38]
miRNA-30d	miR-30d is found enriched in feces of patients with untreated MS. Synthetic miR-30d given orally ameliorates the effects of experimental autoimmune encephalomyelitis (EAE, model of MS) in mice miRNA-30d is identified to suppress the MEK/ERK and PI3K/Akt pathways, and this supports a role of MAPKERK in MS	[39, 40]
miRNA-101	MicroRNA-101 participates in the regulation of MAPKs as it targets MAPK Phosphatase-1 (MKP-1). As negative feedback control enzyme system, MKP-1 also dephosphorylates MAPKERK besides MAPKp38 In patients with MS miRNA-101 has been identified, in particular in those with RRMS	[41–44]
miRNA-145	Dual-specificity phosphatase 6 (DUSP6, or MKP3) is a cytoplasmic phosphatase with high specificity for MAPKERK extracellular signal-regulated kinase (ERK) miRNA-145 is identified to target directly DUSP6 The miR-145 appears up-regulated in MS, in PBMC as well as in MS lesions p53 expression is higher in MS lesions, and this p53 can lead to miR-145 upregulation. By this, DUSP6 can be targeted which leads to lower negative feedback on MAPKERK	[45–49] [50] [50, 51] [48, 49, 52] [52]
miRNA-146a	Analysis of miRNA in CSF and active lesions in patients with MS show upregulation of miR-146a and miR-146b Transcription of miR-146a and miR-146b appears upregulated via different MAP kinase pathways. miR-146b expression is MAPKJNK1/2 and MAPKERK dependent miRNA-146a is upregulated by the EBV encoded protein LMP-1. Both are linked to MAPKERK activity	[37, 51] [53, 54]
miRNA-219	In chronic MS lesions miR-219 is found downregulated In GBM samples miRNA-219-5p was found to inhibit RAS-MAPK and PI3K pathways	[55, 56]
miRNA-221	miR-221-3p is found in higher levels in blood of MS patients. Its expression may relate to neurogenesis in the context of neural regulation The MAPKERK activity was found to promote an increase in miR-221	[57, 58]
miRNA-338	miRNA-338 is downregulated in chronic MS lesions This miRNA inhibits the MAPKERK-signaling pathway: when overexpressed in GBM a lower expression of MEK-2 and ERK-1 was observed	[55] [59]
miRNA-564	In patients with MS, miRNA-564 has been identified to be downregulated in T-cells (whether any level of this miRNA is lymphocytogenic or whether it originates from intercellular exchange is not analyzed) miRNA-564 has been identified to target pERK	[60–62]