Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content

Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons. Abnormal myelin sheath is associated with many neurological diseases. Meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) plays an important role in vesicle trafficking from the endoplasmic reticulum (ER) to Golgi, and conditional knockout (cKO) of Mea6 in the brain significantly affects neural development and brain function. However, whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear. In this study, by using different models of diffusion magnetic resonance imaging, we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter, as well as a significant decrease of cholesterol and triglycerides in brains. Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome, especially the proportion of very long-chain fatty acids (VLCFAs). In particular, the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice. The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long-chain fatty acids (ELOVLs ). Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath, myelin lipids, and the pathogenesis of white matter diseases.