Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination

Publication date: 5 June 2018
Source:Cell Reports, Volume 23, Issue 10
Author(s): Alejandro Alvarez-Prats, Ivana Bjelobaba, Zane Aldworth, Takashi Baba, Daniel Abebe, Yeun Ju Kim, Stanko S. Stojilkovic, Mark Stopfer, Tamas Balla
Active membrane remodeling during myelination relies on phospholipid synthesis and membrane polarization, both of which are known to depend on inositol phospholipids. Here, we show that sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions. Surprisingly, prolonged inhibition of PI4KA in immortalized mouse SCs failed to decrease plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) levels or PI 3-kinase (PI3K) activation, in spite of large reductions in plasma membrane PI4P levels. Instead, it caused rearrangements of the actin cytoskeleton, which was also observed in sciatic nerves of knockout animals. PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor. These studies define a role for PI4KA in myelin formation primarily affecting metabolism of key phospholipids and the actin cytoskeleton.

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Teaser

Alvarez-Prats et al. show that Schwann cell (SC)-specific inactivation of PI4KA in mice causes myelination defects in peripheral nerves, decreases in key phospholipid myelin components, and gross alterations in actin architecture. The results point to impaired phospholipid and actin defects as the primary cause of the myelination defects.


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