TY - JOUR
T1 - Multiple sclerosis is linked to MAPKERK overactivity in microglia
AU - ten Bosch, George J. A.
AU - Bolk, Jolande
AU - ‘t Hart, Bert A.
AU - Laman, Jon D.
N1 - Funding Information: This work has gained impetus by discussions with Professor Anneke Brand (Leiden University Medical Center, Leiden, the Netherlands), Professor Rien Vermeulen (Amsterdam University Medical Center Amsterdam, the Netherlands), and by the technical contribution by Dr. Maurits van den Nieuwboer (FFund Inc., Abcoude, the Netherlands). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - 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 (MAPKERK). 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 MAPKERK. 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 MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK 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 MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.
AB - 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 (MAPKERK). 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 MAPKERK. 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 MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK 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 MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.
KW - DUSP6
KW - Demyelination
KW - LMP-1
KW - MAPK ; Multiple sclerosis
KW - Microglia
UR - http://www.scopus.com/inward/record.url?scp=85105855931&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00109-021-02080-4
DO - https://doi.org/10.1007/s00109-021-02080-4
M3 - Review article
C2 - 33948692
SN - 0946-2716
VL - 99
SP - 1033
EP - 1042
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 8
ER -