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

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

Author information

1
Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, 37075, Germany. fledrich@em.mpg.de.
2
Institute of Anatomy, University of Leipzig, Leipzig, 04103, Germany. fledrich@em.mpg.de.
3
Department of Neuropathology, University Hospital Leipzig, Leipzig, 04103, Germany. fledrich@em.mpg.de.
4
Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, 37075, Germany.
5
Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, 37075, Germany.
6
Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Division, National Research Centre, Giza, 12622, Egypt.
7
Center for Molecular Neurobiology, Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20251, Germany.
8
Department of Neuropathology, University Hospital Leipzig, Leipzig, 04103, Germany.
9
Heidelberg University Biochemistry Center (BZH), Heidelberg, 69120, Germany.
10
Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, 37075, Germany.
11
Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, 37075, Germany.
12
Institute of Neuropathology, University Hospital Aachen, Aachen, 52074, Germany.
13
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, Wuerzburg, 97080, Germany.
14
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, 37075, Germany.
15
German Center for Neurodegenerative Diseases, Tübingen, 72076, Germany.
16
Institute of Anatomy, University of Leipzig, Leipzig, 04103, Germany.
17
Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, 37075, Germany. nave@em.mpg.de.
18
Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, 37075, Germany. stassart@em.mpg.de.
19
Department of Neuropathology, University Hospital Leipzig, Leipzig, 04103, Germany. stassart@em.mpg.de.
20
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, 37075, Germany. stassart@em.mpg.de.
21
Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, 37075, Germany. sereda@em.mpg.de.
22
Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, 37075, Germany. sereda@em.mpg.de.

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.

PMID:
30072689
PMCID:
PMC6072747
DOI:
10.1038/s41467-018-05420-0
[Indexed for MEDLINE]
Free PMC Article

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