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.
Highlights
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
The observed transcriptional dysregulation in CMT1A strongly correlates with the time course of myelin biosynthesis, and no major changes of gene transcription were observed at embryonic day 21 (Fig. 1a)
CMT1A is characterized by dysmyelination during early postnatal development along with a slowly progressive demyelination and axonal loss in adult peripheral nerves
Summary
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. 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. In a comparative transcriptomic analysis using microarrays between mildly and severely affected CMT rats at early (P6) and late (P90) time points, we found the lipidassociated genes to be differentially expressed between mildly and severely affected CMT rats, which allowed us to derive surrogate biomarkers for disease severity[22,64] This led to the hypothesis that Pmp[22] overexpression in CMT1A disease and disturbed intracellular lipid metabolism interfere with myelin biogenesis and cause the dysmyelinating phenotype. Schwann cells respond to internal and external changes of lipid metabolism, rendering lipid supplementation an attractive therapeutic option in diseases such as CMT1A
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