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

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

doi:10.1101/2023.04.02.535224

NeurosciencebioRxivApr 2, 2023

Preprint

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

Robert Ciarán Prior iD, Alessio Silva iD, Tim Vangansewinkel iD, Jakub Idkowiak iD, Arun Kumar Tharkeshwar iD, Tom P. Hellings iD, Iliana Michailidou iD, Jeroen P. Vreijling iD, Maarten Loos iD, Bastijn Koopmans iD, Nina Vlek, Nina Straat, Cedrick Agaser, Thomas B. Kuipers iD, Christine Michiels iD, Elisabeth Rossaert iD, Stijn Verschoren iD, Wendy Vermeire, Vincent de Laat iD, Jonas Dehairs iD, Kristel Eggermont iD, Diede van den Biggelaar, Adekunle T. Bademosi iD, Frédéric A. Meunier iD, Martin vandeVen iD, , Ludo Van Den Bosch iD

Abstract

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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/535224v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@17d4e84org.highwire.dtl.DTLVardef@1adce4forg.highwire.dtl.DTLVardef@1c3e1eborg.highwire.dtl.DTLVardef@12525da_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPMP22 copy number causes a dose-dependent suppression of cholesterol and lipid biosynthesis in peripheral nerves of CMT1A mice C_LIO_LILipid 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 C_LIO_LICMT1A iPSC-SCPs show decreased plasma membrane lipids required for regulating lipid raft dynamics, membrane fluidity, and membrane order C_LIO_LILipid storage misregulation is key in the pathogenesis of CMT1A C_LI

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