PI4KA controls the levels of key lipids important for myelination in Schwann cells independently from the PI3K/Akt/mTOR pathway

Authors

• A ALVAREZ-PRATS
• YJ KIM
• T BALLA

Abstract

Myelin is a key component of the nervous system essential for proper propagation of electrical signals along the axons. In the peripheral nervous system myelination is carried out by Schwann cells (SCs). Here, we show that prolonged inhibition of PI4KA in SCs dramatically affects the amounts of phospholipids that are specifically important components of the myelin but did not affect the downstream PI3K/Akt/mTOR signaling axis, which is also required for proper myelination. SCs were treated with 100 nM A1, a potent and specific PI4KA inhibitor, or DMSO for 24 h, and lipidomic analysis was performed. In parallel experiments, we investigated the effect of similar treatment on the response of the PI3K/Akt/mTOR pathway to stimulation with serum by following the phosphorylation of Akt and of p70 S6-kinase, a target of mTOR. We also followed the levels of the phosphoinositides, PI4P and PI(4,5)P2 by confocal microscopy. Our results showed that inhibition of PI4KA eliminated PI4P from the plasma membrane without notable change in the amount of plasma membrane PI(4,5)P2 nor in PI3K activation. In contrast, a significant reduction in the level of selected phospholipids: phosphatidylserine, phosphatidylethanolamine, and sphingomyelin, major lipid components of the myelin, was observed. In summary, these studies suggest that the primary mechanism by which PI4KA is important for myelination is not by maintaining PI(4,5)P2 levels in the plasma membrane and supporting the PI3K/Akt/mTOR pathway. Instead, the enzyme is needed for the synthesis and distribution of selected major phospholipids that are basic lipid components of the myelin.

Scientific Focus Area: Neuroscience

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