Longitudinal analysis of lipid changes in the sciatic nerve caused by overexpression of PMP22 in murine models of CMT1A.

Abstract

Charcot-Marie-Tooth type 1A (CMT1A), a prevalent progressive demyelinating peripheral neuropathy is caused by a duplication of the peripheral myelin protein (PMP22) gene. PMP22 is crucial for formation of compact myelin, but the mechanism by which PMP22 overexpression results in CMT1A pathogenesis remains elusive. Emerging evidence points to the role of PMP22 in lipid metabolism as a key modulator of disease progression. Here we show that C3 and C22 mouse models, carrying 5 and 10 additional copies of the human PMP22 gene, have PMP22 dose-dependent lipidomic and transcriptomic alterations. Both models show a decrease in membrane-associated lipids (e.g. phospholipids and sphingolipids) and an increase in neutral lipids (e.g. cholesteryl esters) from three weeks of age. Notably, while cholesteryl ester concentrations are elevated, particularly in C22 mice, total cholesterol levels were significantly reduced, accompanied by the downregulation of key genes involved in cholesterol biosynthesis. Significant decreases were also observed in phospholipids and sphingolipids, including ceramide and sphingomyelin, with a proportional shift towards shorter fatty acid chains in sphingomyelin due to altered ceramide synthase expression. Plasmalogen concentrations decreased with shifts in the proportion of specific plasmalogen species, aligning with impaired synthesis. These lipidomic changes, impacting myelin-associated lipids and fatty acid compositions, underscore their critical role in the dysmyelination observed in CMT1A. Our findings suggest potential avenues for dietary interventions, such as specific fatty acid and plasmalogen supplementation to improve myelination in CMT1A.