CTL1 (SLC44A1) regulates myelin lipid composition and architecture in Schwann cells

CTL1, also known as SLC44A1, is a protein that plays a crucial role in the regulation of myelin lipid composition and architecture in Schwann cells. Myelin formation necessitates the synthesis of a large number of membrane lipids; however, the mechanism by which myelinating glia acquire choline - a vital component for this process - is not well understood.

Choline transporter-like protein 1 (CTL1) is abundantly expressed in Schwann cells, and its deficiency in oligodendrocytes leads to impaired CNS myelination. In this study, researchers investigated the impact of CTL1 on peripheral nerve myelination using Schwann cell-specific Ctl1 knockout mice. To their surprise, they found that the loss of Ctl1 did not affect Schwann cell differentiation, the number of myelinated axons, or myelin thickness.

Nonetheless, they observed an increase in myelin abnormalities, such as in-foldings and out-foldings. A lipidomic analysis revealed selective alterations in the composition of myelin lipids, particularly in long-chain lipid species, along with triglyceride accumulation in the entire nerves. Furthermore, CTL1 deficiency led to an increase in mTORC1-associated S6 and mTORC2-associated AKT S473 phosphorylation.

Transcriptomic analysis showed downregulation of gene programs associated with fatty acid β-oxidation, triglyceride catabolism, and oxidative phosphorylation. Following peripheral nerve injury, Ctl1-deficient Schwann cells displayed a normal repair response and efficiently remyelinated regenerated axons despite the altered mTOR signaling.

These findings suggest that CTL1 is not necessary for the overall production of peripheral myelin; instead, it contributes to maintaining normal myelin lipid composition and architecture. This discovery uncovers an unexpected ability of Schwann cells to sustain myelination despite disruptions in CTL1-dependent choline metabolism.