Paper

Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A

Van Damme, Philip, Lambrichts, Ivo, Agaser, Cedrick, Fluiter, Kees, Vangansewinkel, Tim, Silva, Alessio, Baas, Frank, Michiels, Christine, Rossaert, Elisabeth, Hellings, Tom P., Meunier, Frederic A., Swinnen, Johannes V., Tharkeshwar, Arun Kumar, Straat, Nina, de Laat, Vincent, Prior, Robert, Vermeire, Wendy, Koopmans, Bastijn, Vlek, Nina, Mei, Hailiang, Verschoren, Stijn, Wolfs, Esther, Michailidou, Iliana, van den Biggelaar, Diede, Den Bosch, Ludo Van, Eggermont, Kristel, Loos, Maarten, Bademosi, Adekunle T., Idkowiak, Jakub, Dehairs, Jonas, vandeVen, Martin, Vreijling, Jeroen, Kuipers, Tom

2023

Overview

Duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A) and is known to disrupt the lipid metabolism in myelinating Schwann cells by unknown mechanisms. By using two CMT1A mouse models overexpressing human PMP22, we discovered that PMP22 dose-dependently downregulates genes that are involved in lipid and cholesterol metabolism. Lipidomic analysis on CMT1A mouse sciatic nerves confirmed lipid metabolic abnormalities primarily associated with cholesterol and sphingolipids. We observed similar lipidomic profiles and downregulation of genes associated with lipid metabolism in human CMT1A patient induced pluripotent stem cell-derived Schwann cell precursors (iPSC-SCPs). We confirmed these findings by demonstrating altered lipid raft dynamics and plasma membrane fluidity in CMT1A iPSC-SCPs. Additionally, we identified impaired cholesterol incorporation in the plasma membrane due to altered lipid storage homeostasis in CMT1A iPSC-SCPs, which could be modulated by changing the lipid composition of the cell culture medium. These findings suggest that PMP22 plays a role in regulating the lipid composition of the plasma membrane and lipid storage homeostasis. Targeting lipid metabolism may hold promise as a potential treatment for CMT1A patients. PMP22 copy number causes a dose-dependent suppression of cholesterol and lipid biosynthesis in peripheral nerves of CMT1A mice Lipid composition is altered in the sciatic nerves of CMT1A mice and in the membranes of patient derived iPSC-SCPs, with a significant reduction in sphingolipids CMT1A iPSC-SCPs show decreased plasma membrane lipids required for regulating lipid raft dynamics, membrane fluidity, and membrane order Lipid storage misregulation is key in the pathogenesis of CMT1A

• Publisher: Cold Spring Harbor Laboratory
• Subject: Neuroscience