p38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions

• Published in: Brain (London, England : 1878) England : 1878), 2024-05, Vol.147 (5), p.1871-1886
• Main Authors: Marziali, Leandro N, Hwang, Yoonchan, Palmisano, Marilena, Cuenda, Ana, Sim, Fraser J, Gonzalez, Alberto, Volsko, Christina, Dutta, Ranjan, Trapp, Bruce D, Wrabetz, Lawrence, Feltri, Maria L
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; Cuprizone - toxicity; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase 12 - genetics; Mitogen-Activated Protein Kinase 12 - metabolism; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Myelin Sheath - metabolism; Myelin Sheath - pathology; Oligodendrocyte Precursor Cells - metabolism; Oligodendrocyte Precursor Cells - pathology; Oligodendroglia - metabolism; Oligodendroglia - pathology; Remyelination - physiology
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awad421

Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.