PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells

Robert Prior; Alessio Silva; Tim Vangansewinkel; Jakub Idkowiak; Arun Kumar Tharkeshwar; Tom P Hellings; Iliana Michailidou; Jeroen Vreijling; Maarten Loos; Bastijn Koopmans; Nina Vlek; 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; Frederic A Meunier; Martin vandeVen; Philip Van Damme; Hailiang Mei; Johannes V Swinnen; Ivo Lambrichts; Frank Baas; Kees Fluiter; Esther Wolfs; Ludo Van Den Bosch

doi:10.1093/brain/awae158

PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells

Brain. 2024 May 14:awae158. doi: 10.1093/brain/awae158. Online ahead of print.

Authors

Robert Prior^{1

2

3}, Alessio Silva^{1

2}, Tim Vangansewinkel^{2

4}, Jakub Idkowiak^{5

6}, Arun Kumar Tharkeshwar^{1

2}, Tom P Hellings⁷, Iliana Michailidou⁷, Jeroen Vreijling⁷, Maarten Loos⁸, Bastijn Koopmans⁸, Nina Vlek⁸, Cedrick Agaser⁹, Thomas B Kuipers⁹, Christine Michiels^{1

2}, Elisabeth Rossaert^{1

2}, Stijn Verschoren^{1

2}, Wendy Vermeire^{1

2}, Vincent de Laat⁵, Jonas Dehairs⁵, Kristel Eggermont^{1

2}, Diede van den Biggelaar^{1

2}, Adekunle T Bademosi¹⁰, Frederic A Meunier^{10

11}, Martin vandeVen⁴, Philip Van Damme^{1

2

12}, Hailiang Mei⁹, Johannes V Swinnen⁵, Ivo Lambrichts⁴, Frank Baas⁷, Kees Fluiter⁷, Esther Wolfs⁴, Ludo Van Den Bosch^{1

2}

Affiliations

¹ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000, Leuven, Belgium.
² VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000, Leuven, Belgium.
³ Department of Ophthalmology, Medical Faculty, University of Bonn, 53127, Bonn, Germany.
⁴ UHasselt - Hasselt University, Biomedical Research Institute, 3590, Diepenbeek, Belgium.
⁵ Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, 3000, Leuven, Belgium.
⁶ Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, 532 10, Pardubice, Czech Republic.
⁷ Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
⁸ Sylics (Synaptologics BV), Antonie van Leeuwenhoeklaan 9, 3721 MA, Bilthoven, The Netherlands.
⁹ Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
¹⁰ Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia.
¹¹ School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Queensland, Australia.
¹² University Hospitals Leuven, Department of Neurology, 3000, Leuven, Belgium.

PMID: 38743588
DOI: 10.1093/brain/awae158

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 megabase tandem duplication of chromosome 17 harboring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To get better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication on cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was dose-dependently downregulated throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signaling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity, and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane due to an alteration in the lipid composition, which ultimately may lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of CMT1A patients.

Keywords: CMT1A; Schwann cells; autophagy; human iPSCs; lipid metabolism; lipid storage; plasma membrane.