. 2021 May 5;99(8):1033–1042. doi: 10.1007/s00109-021-02080-4

Table 1.

Examples of biochemical associations between MS and the MAPK^ERK pathway

Parameter	Association	References
Wnt/β-catenin	Reduction in Wnt/β-catenin signaling in microglia leads to a microglial phenotype causing hypomyelination This Wnt/β-catenin signaling is downregulated by overactivity of the MAPK^ERK pathway	[8, 9]
MSK1	The mitogen- and stress-activated kinase 1 (MSK1) phosphorylates pro-inflammatory nuclear factor NF-κB p65. MSK1 is activated by MAPK^ERK and MAPK^p38 MS-medicine dimethyl fumarate (Tecfidera®) is known to inhibit MSK1 besides counteracting oxidative stress, also in microglia	[10–12]
MC1r	The melanocortin 1 receptor (MC1r), also expressed on microglia, is involved in signal transduction and development. In comparison with default ligand α-MSH, [Nle⁴, DPhe⁷]-α-MSH leads to inhibition of phosphorylation of ERK This [Nle⁴, DPhe⁷]-α-MSH appeared neuroprotective in murine models of neuroinflammation	[13, 14]
Notch1	Activation of Notch1 by ligands Jagged1 or contactin are associated with decreased oligodendrocyte precursor cells and demyelination in MS Expression of these ligands seems linked to MAPK^ERK induced TGFβ (leads to Jagged1), and to MAPK^ERK activity–dependent contactin1, respectively	[15–18] [18, 19]
MITF	Myelin basic protein (MBP) gene expression appears regulated by microphthalmia-associated transcription factor (MITF) Sustained ERK phosphorylation stimulates degradation of MITF, thus overactive MAPK^ERK may hinder expression of MBP	[19, 20]
DHODH	Teriflunomide (Aubagio®, drug registered for MS) inhibits dihydro-orotate dehydrogenase (DHODH), a key enzyme in the pyrimidine synthesis pathway DHODH is regulated at the level of carbamoyl-phosphate synthetase(CAD), an enzyme activated by MAPK^ERK phosphorylation Therefore, as cytokine production is dependent on DHODH-directed pyrimidine synthesis and the functioning of CAD/DHODH is lowered by teriflunomide in microglia, this may point to activity of MAPK^ERK in MS	[21–23]
VCAM-1	Inhibition of the MAPK^ERK pathway downregulates the expression of vascular cell adhesion molecule 1 (VCAM-1), ligand for integrin α4β1. As a key adhesion molecule integrin α4β1 induces the translocation of leukocytes to inflamed tissue. This demonstrates a role of the MAPK^ERK in activating this integrin, also in microglia Therefore, controlling overactivity in the MAPK^ERK pathway may result in a similar limitation of integrin α4β1 activation as applying by α4β1-antagonist MoAb natalizumab (Tysabri®, medicine for MS)	[24–26]
NfL	Activation of MAPK^ERK (and also MAPK^p38) leads to expression of Neurofilament light (NfL) protein As the expression level of NfL is positively associated with the level of MS disease activity (relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score) the activity of MAPK^ERK (and also MAPK^p38) relates to MS	[27, 28]
GFAP	GFAP (Glial Fibrillary Acidic Protein) is known to participate in glial scarring as a consequence of neurodegenerative conditions. It is an established biomarker of neurodegeneration in MS, besides NfL In 2013 it was observed that preventing MAPK^ERK activation antagonized IL-1β-induced GFAP expression, whereas overactive MAPK^ERK appeared to contribute to expression of GFAP	[29–32]
MMP-9	MMP-9 (matrix metalloproteinase 9) is involved in blood-brain barrier disruption and formation of MS lesions. In patients with MS, the expression of MMP-9 is substantially higher when compared with controls, and it can be considered biomarker for disease severity MMP-9 expression occurs in response to activation of the MAPK^ERK pathway	[33–35]