SLC44A1 deficiency impedes myelin development in the central nervous system

Systematic lipidomic profiling of myelin sheaths reveals altered phospholipid composition in SLC44A1-deficient mice

We hypothesized that SLC44A1, a choline transporter highly expressed in mature oligodendrocytes, is essential for maintaining myelin lipid composition and that its deficiency disrupts phospholipid biosynthesis, leading to hypomyelination.

To test this, we performed lipidomic analysis on myelin sheaths isolated from the whole brains of control and oligodendrocyte-specific Slc44a1 conditional knockout (Slc44a1 cKO) mice at postnatal day 21. Myelin was purified using discontinuous sucrose gradient ultracentrifugation, and lipids were extracted using a modified Bligh and Dyer method. Lipidomic profiling was conducted using normal-phase HPLC coupled with tandem mass spectrometry (Sciex QTRAP 6500 PLUS), enabling quantitative assessment of diverse lipid classes.

Our data demonstrate a significant reduction in multiple lipid species within the myelin of Slc44a1 cKO mice. Notably, phosphatidylcholines (PCs)—the most abundant phospholipids in myelin—were markedly decreased, along with sulfatides, alkyl phosphatidylethanolamines, phosphatidylethanolamines (PE), and phosphatidylserines. Heatmap and compositional analyses revealed that PCs with varying chain lengths and saturation levels were consistently reduced. Among the top 10 most significantly downregulated lipids, PCs constituted the majority, underscoring a specific defect in PC metabolism.

These lipidomic alterations are consistent with our transcriptomic and metabolomic findings, which indicated impaired choline metabolism and citicoline biosynthesis in SLC44A1-deficient oligodendrocytes. The data support the interpretation that SLC44A1 facilitates choline uptake necessary for phosphatidylcholine synthesis, and its loss disrupts myelin lipid architecture, contributing to the observed hypomyelination phenotype.

The lipidomics dataset provides a comprehensive resource for understanding myelin lipid dynamics in neurodevelopmental disorders and may serve as a reference for future studies on lipid metabolism in oligodendrocyte biology and myelin-related diseases.