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PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells
R. Prior, A. Silva, T. Vangansewinkel, J. Idkowiak, AK. Tharkeshwar, TP. Hellings, I. Michailidou, J. Vreijling, M. Loos, B. Koopmans, N. Vlek, C. Agaser, TB. Kuipers, C. Michiels, E. Rossaert, S. Verschoren, W. Vermeire, V. de Laat, J. Dehairs,...
Language English Country England, Great Britain
Document type Journal Article
Grant support
VIB
KU Leuven
Fonds voor Wetenschappelijk Onderzoek
NHMRC
W.OR14-09
Prinses Beatrix Spierfonds
NLK
Free Medical Journals
from 1996 to 1 year ago
Open Access Digital Library
from 1996-01-01
PubMed
38743588
DOI
10.1093/brain/awae158
Knihovny.cz E-resources
- MeSH
- Cell Membrane * metabolism MeSH
- Charcot-Marie-Tooth Disease * genetics metabolism pathology MeSH
- Gene Duplication MeSH
- Homeostasis * physiology MeSH
- Induced Pluripotent Stem Cells * metabolism MeSH
- Humans MeSH
- Lipid Metabolism * physiology MeSH
- Myelin Proteins * metabolism genetics MeSH
- Mice MeSH
- Sciatic Nerve metabolism MeSH
- Schwann Cells * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in 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 (RNA-seq) 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 downregulated in a dose-dependent manner 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 signalling. 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 owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A.
Department of Clinical Genetics Leiden University Medical Center Leiden 2333 ZA The Netherlands
Department of Neurology University Hospitals Leuven Leuven 3000 Belgium
Department of Ophthalmology Medical Faculty University of Bonn Bonn 53127 Germany
InnoSer Nederland B 5 2333 CK Leiden The Netherlands
Laboratory of Lipid Metabolism and Cancer Department of Oncology KU Leuven Leuven 3000 Belgium
Laboratory of Neurobiology VIB Center for Brain and Disease Research Leuven 3000 Belgium
School of Biomedical Sciences The University of Queensland Brisbane QLD 4072 Australia
UHasselt Hasselt University Biomedical Research Institute Diepenbeek 3590 Belgium
References provided by Crossref.org
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