Proteomics‐level analysis of myelin formation and regeneration in a mouse model for Vanishing White Matter disease

Vanishing white matter (VWM) is a recessive neurodegenerative disease caused by mutations in translation initiation factor eIF2B and leading to progressive brain myelin deterioration, secondary axonal damage, and death in early adolescence. Eif2b5^R132H/R132H mice exhibit delayed developmental myelination, mild early neurodegeneration and a robust remyelination defect in response to cuprizone‐induced demyelination. In the current study we used Eif2b5^R132H/R132H mice for mass‐spectrometry analyses, to follow the changes in brain protein abundance in normal‐ versus cuprizone‐diet fed mice during the remyelination recovery phase. Analysis of proteome profiles suggested that dysregulation of mitochondrial functions, altered proteasomal activity and impaired balance between protein synthesis and degradation play a role in VWM pathology. Consistent with these findings, we detected elevated levels of reactive oxygen species in mutant‐derived primary fibroblasts and reduced 20S proteasome activity in mutant brain homogenates. These observations highlight the importance of tight translational control to precise coordination of processes involved in myelin formation and regeneration and point at cellular functions that may contribute to VWM pathology.