Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy

Nat Commun. 2018 Aug 2;9(1):3025. doi: 10.1038/s41467-018-05420-0.

Abstract

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / ultrastructure
  • Charcot-Marie-Tooth Disease / therapy*
  • Dietary Fats / pharmacology
  • Lipid Metabolism* / drug effects
  • Lipids / biosynthesis
  • Myelin Sheath / metabolism*
  • Myelin Sheath / ultrastructure
  • Phospholipids / metabolism
  • Rats, Transgenic
  • Schwann Cells / drug effects
  • Schwann Cells / metabolism
  • Schwann Cells / pathology

Substances

  • Dietary Fats
  • Lipids
  • Phospholipids