Cholesterol inserted into the myelin bilayer increases viscosity, and cooperates with other lipids and proteins to improve myelin stability. Although cholesterol, phospholipids, and glycolipids are the most abundant lipid species in all biological membranes, the content of cholesterol in myelin (~40%) is much higher than in other membrane structures (~25%) while phospholipid is lower (~40% versus ~65%). After initiating myelination, oligodendrocytes rapidly expand their surface area and synthesize large amounts of lipids in a short period, forming a special tightly wrapped lipid bilayer structure, named myelin sheath. White matter is predominantly composed of lipid-rich mature oligodendrocytes which spirally wrap neuronal axons. White matter dysfunction is associated with a variety of neurological disorders, such as X-linked leukodystrophies, multiple sclerosis, Alzheimer’s disease, and schizophrenia. More than half of adult human brain is made up of white matter. During development, white matter expands around the corpus callosum (CC) and embeds in the gray matter. In addition to gray matter (neuron-rich regions), an increase in white matter volume during development is also important for brain function. Mea6, oligodendrocyte, hypomyelination, myelin lipidomic analysis Introduction 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. The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids ( ELOVLs). In particular, the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice. 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 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. However, whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear. 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. Abnormal myelin sheath is associated with many neurological diseases. Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.
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