Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy
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Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy. / Fledrich, R; Abdelaal, T; Rasch, L; Bansal, V; Schütza, V; Brügger, B; Lüchtenborg, C; Prukop, T; Stenzel, J; Rahman, R U; Hermes, D; Ewers, D; Möbius, W; Ruhwedel, T; Katona, I; Weis, J; Klein, D; Martini, R; Brück, W; Müller, W C; Bonn, S; Bechmann, I; Nave, K A; Stassart, R M; Sereda, M W.
In: NAT COMMUN, Vol. 9, No. 1, 02.08.2018, p. 3025.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy
AU - Fledrich, R
AU - Abdelaal, T
AU - Rasch, L
AU - Bansal, V
AU - Schütza, V
AU - Brügger, B
AU - Lüchtenborg, C
AU - Prukop, T
AU - Stenzel, J
AU - Rahman, R U
AU - Hermes, D
AU - Ewers, D
AU - Möbius, W
AU - Ruhwedel, T
AU - Katona, I
AU - Weis, J
AU - Klein, D
AU - Martini, R
AU - Brück, W
AU - Müller, W C
AU - Bonn, S
AU - Bechmann, I
AU - Nave, K A
AU - Stassart, R M
AU - Sereda, M W
PY - 2018/8/2
Y1 - 2018/8/2
N2 - 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.
AB - 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.
KW - Animals
KW - Axons
KW - Charcot-Marie-Tooth Disease
KW - Dietary Fats
KW - Lipid Metabolism
KW - Lipids
KW - Myelin Sheath
KW - Phospholipids
KW - Rats, Transgenic
KW - Schwann Cells
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/s41467-018-05420-0
DO - 10.1038/s41467-018-05420-0
M3 - SCORING: Journal article
C2 - 30072689
VL - 9
SP - 3025
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -