Onderzoek naar verstoorde lipidenstofwisseling bij Charcot-Marie-Tooth-ziekte type 1A

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by a chromosomal duplication that results in PMP22 overexpression. Because Schwann cells require tightly regulated lipid synthesis, storage, and plasma membrane organization to support myelination, we investigated how increased PMP22 dosage disrupts lipid homeostasis during Schwann cell development and how these metabolic alterations contribute to peripheral nerve pathology. To characterize lipid changes in vivo, we performed quantitative lipidomics on mouse sciatic nerves and found a broad depletion of multiple lipid classes in CMT1A mice, including reduced cholesterol and dysregulated sphingolipids, consistent with developmental dysmyelination and demyelination. To determine whether lipid defects develop early in the Schwann cell lineage in a human context, patient-derived iPSCs were differentiated into Schwann cell precursors (iPSC-SCPs) and compared to isogenic healthy controls. CMT1A iPSC-SCPs exhibited significant remodeling of membrane lipid composition, characterized by reduced cholesterol and sphingomyelin and a shift toward polyunsaturated fatty acid (PUFA)-enriched phospholipids. These changes were associated with decreased plasma membrane order and impaired cholesterol incorporation, and were reversed by pharmacological stimulation of cholesterol redistribution from intracellular stores, implicating altered lipid trafficking as a therapeutically targetable mechanism. Under lipid stress, CMT1A iPSC-SCPs showed abnormal regulation of lipid storage and handling, with an altered response to lipid starvation and excessive lipid droplet accumulation upon lipid overstimulation. To connect lipid remodeling with the stress response of peripheral nerves, transcriptional and protein analyses revealed suppression of de novo lipogenesis and defective cholesterol transport in CMT1A sciatic nerves, together with imbalanced antioxidants. Finally, targeted mediator lipidomics identified an accumulation of oxylipins in CMT1A nerves. These are PUFA-derived lipid mediators generated through multiple pathways, including 12/15-lipoxygenase, which was increased predominantly in endoneurial macrophages, linking lipid dysregulation to inflammatory signaling. Altogether, our findings show that PMP22 overexpression disrupts lipid homeostasis early in Schwann cell development, impairs membrane organization and lipid handling, and is connected to macrophage-associated oxylipin pathways, highlighting lipid trafficking and immune-metabolic axes as therapeutic targets in CMT1A.