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

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. To investigate these mechanisms, we analyzed the C3 and C22 mouse models, carrying 5 and 10 additional copies of the human PMP22 gene, at five developmental stages (3, 5, 7, 9, and 12 weeks of age). We focused on alterations in lipid synthesis associated with PMP22 overexpression and disease progression, and found a clear gene-dosage effect. In addition, we examined mice on the C3 background with a Schwann cell–specific c-Jun knockout. Our findings suggest potential avenues for dietary interventions, to improve myelination in CMT1A.