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

R. Fledrich (), T. Abdelaal, L. Rasch, V. Bansal, V. Schütza, B. Brügger, C. Lüchtenborg, T. Prukop, J. Stenzel, R. U. Rahman, D. Hermes, D. Ewers, W. Möbius, T. Ruhwedel, I. Katona, J. Weis, D. Klein, R. Martini, W. Brück, W. C. Müller, S. Bonn, I. Bechmann, K. A. Nave (), R. M. Stassart () and M. W. Sereda ()
Additional contact information
R. Fledrich: Max-Planck-Institute of Experimental Medicine
T. Abdelaal: Max-Planck-Institute of Experimental Medicine
L. Rasch: Max-Planck-Institute of Experimental Medicine
V. Bansal: University Medical Center Hamburg-Eppendorf
V. Schütza: Max-Planck-Institute of Experimental Medicine
B. Brügger: Heidelberg University Biochemistry Center (BZH)
C. Lüchtenborg: Heidelberg University Biochemistry Center (BZH)
T. Prukop: Max-Planck-Institute of Experimental Medicine
J. Stenzel: Max-Planck-Institute of Experimental Medicine
R. U. Rahman: University Medical Center Hamburg-Eppendorf
D. Hermes: Max-Planck-Institute of Experimental Medicine
D. Ewers: Max-Planck-Institute of Experimental Medicine
W. Möbius: Max-Planck-Institute of Experimental Medicine
T. Ruhwedel: Max-Planck-Institute of Experimental Medicine
I. Katona: University Hospital Aachen
J. Weis: University Hospital Aachen
D. Klein: University Hospital Wuerzburg
R. Martini: University Hospital Wuerzburg
W. Brück: University Medical Center Göttingen
W. C. Müller: University Hospital Leipzig
S. Bonn: University Medical Center Hamburg-Eppendorf
I. Bechmann: University of Leipzig
K. A. Nave: Max-Planck-Institute of Experimental Medicine
R. M. Stassart: Max-Planck-Institute of Experimental Medicine
M. W. Sereda: Max-Planck-Institute of Experimental Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05420-0

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