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Immunofluorescence Staining Using IBA1 and TMEM119 for Microglial Density, Morphology and Peripheral Myeloid Cell Infiltration Analysis in Mouse Brain
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Multiple sclerosis is linked to MAPKERK overactivity in microglia

George J A Ten Bosch1, Jolande Bolk2, Bert A 't Hart3,4

  • 1Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. gjatenbosch2019@outlook.com.

Journal of Molecular Medicine (Berlin, Germany)
|May 5, 2021
PubMed

Insights

Multiple sclerosis (MS) may stem from overactive mitogen-activated protein kinase ERK (MAPKERK) in microglia, disrupting myelin. This pathway dysfunction, linked to MS risk factors, offers a new therapeutic target for neurodegeneration.

Area of Science:

  • Neuroimmunology
  • Neurodegeneration
  • Molecular Biology

Background:

  • Multiple sclerosis (MS) pathophysiology is primarily viewed as autoimmune.
  • Microglial dysfunction has been implicated in neurodegenerative processes.
  • Mitogen-activated protein kinase (MAPK) pathways, particularly MAPKERK, are increasingly recognized in neurodegeneration.

Purpose of the Study:

  • To reassess published observations in MS patients to propose a new pathophysiological concept.
  • To investigate the role of microglial mitogen-activated protein kinase ERK (MAPKERK) overactivity in MS.
  • To explore potential novel therapeutic targets for refractory MS.

Main Methods:

  • Reanalysis of existing biochemical and epigenetic data from MS patients.
  • Review of preclinical research on MAPK pathways in neurodegeneration.
  • Correlation of known MS risk factors with MAPKERK pathway regulation.

Main Results:

  • Published data suggest microglial malfunction due to inappropriate MAPKERK overactivity in MS.
  • MAPKERK overactivity in microglia can disturb oligodendrocytes, leading to demyelination.
  • MS risk factors (EBV, hypovitaminosis D, smoking) downregulate MAPKERK negative feedback, potentially causing pathway overactivity.

Conclusions:

  • Microglial MAPKERK overactivity presents a novel pathophysiological concept for MS, distinct from autoimmunity.
  • This pathway dysfunction may explain persistent neurodegeneration in MS patients undergoing treatment.
  • Targeting MAPKERK overactivity in microglia could represent a new therapeutic strategy for progressive and refractory MS.
Keywords:
DUSP6DemyelinationLMP-1MAPKERK; Multiple sclerosisMicroglia

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