Multiple sclerosis is linked to MAPKERK overactivity in microglia

Abstract

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPK^ERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPK^ERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPK^ERK negative feedback phosphatases that normally regulate MAPK^ERK activity. Consequently, these factors may contribute to inappropriate MAPK^ERK overactivity, and thereby to neurodegeneration. Also, MAPK^ERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPK^ERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.

Keywords: DUSP6; Demyelination; LMP-1; MAPKERK; Multiple sclerosis; Microglia.

Fig. 1

a In mice immunized with MOG35–55 peptide, the expression of TAK1 in microglia appeared essential for the development of autoimmune inflammation of the CNS. b Mice with TAK1-deficient microglia were highly resistant to MOG35–55 immunization, which resulted in a considerably less severe disease [1]

Fig. 2

a Ligand binding to surface receptor (e.g. EGF-R) evokes downstream signaling leading to MAPK^ERK activation. b The introduction of BRAF^V600E in mouse microglia leads to substantial overactivation of MAPK^ERK. This resulted in clinical and histopathological substantial neurodegeneration. c Early administration of BRAF^V600E-inhibiting PLX4720 to these mice with BRAF^V600E expressing microglia gave diminished MAPK^ERK activation in these microglia and clinically as well as histopathologically attenuated neurodegeneration [5]

Fig. 3

Under physiological circumstances, the MAPK^ERK is adequately controlled by negative feedback phosphatases, in particular DUSP-6 and also DUSP-1. Epstein Barr virus (EBV)-encoded Latent Membrane Protein-1 (LMP-1) represses these phosphatases in cells with EBV latency [89]. Fingolimod activates protein serine/threonine phosphatase 2A (PP2A) [91], and this can dephosphorylate MAPK^ERK [92]