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. Eif2b5(R132H/R132H) mouse model for vanishing white matter (VWM) disease was used for mass spectrometry of brain
proteins at two time points under normal conditions and along recovery from
cuprizone-induced
demyelination. Comparisons of
proteome profiles revealed the importance of mitochondrial function and tight coordination between
protein synthesis and degradation to myelination formation and regeneration, pointing at cellular functions that contribute to VWM pathology.