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Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content
Tiantian Ma1,2, Wei Mao3,4, Shaohua Zhang1,2
1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
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.
Insights
Meningioma-expressed antigen 6 (Mea6) is crucial for oligodendrocyte development and white matter integrity. Its absence impairs brain white matter microstructure and alters myelin lipid composition, particularly very long chain fatty acids (VLCFAs).
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Myelin sheath, formed by oligodendrocytes, is vital for neuronal function and its abnormalities are linked to neurological diseases.
- Meningioma-expressed antigen 6 (Mea6) is known to be involved in intracellular vesicle trafficking.
- The specific role of Mea6 in oligodendrocyte development and white matter formation remains largely unexplored.
Purpose of the Study:
- To investigate the function of Mea6 in oligodendrocytes and its impact on brain white matter development and lipid composition.
- To elucidate the consequences of Mea6 conditional knockout (cKO) in oligodendrocytes on brain microstructure and myelin lipids.
Main Methods:
- Utilized diffusion magnetic resonance imaging (dMRI) models to assess white matter integrity in Mea6 cKO mice.
- Performed comprehensive lipidomic analysis on purified myelin sheaths.
- Examined the expression levels of genes involved in fatty acid elongation, such as elongation of very long chain fatty acids (ELOVLs).
Main Results:
- Conditional knockout of Mea6 in oligodendrocytes resulted in significant impairments in white matter gross and microstructure.
- Brains of Mea6 cKO mice showed a notable decrease in cholesterol and triglycerides.
- Lipidomic analysis revealed significant alterations in myelin lipid composition, with a marked reduction in very long chain fatty acids (VLCFAs), particularly in phosphatidylcholines.
Conclusions:
- Mea6 plays a critical role in oligodendrocyte development and the maintenance of white matter integrity.
- The absence of Mea6 disrupts myelin lipid homeostasis, specifically affecting VLCFA levels, likely due to downregulated ELOVL expression.
- This study provides valuable insights into the pathogenesis of white matter diseases and the mechanisms underlying myelin lipid formation.
