Enhanced axonal neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot-Marie-Tooth type 1B mouse model.
Animals
Axons
/ metabolism
Charcot-Marie-Tooth Disease
/ etiology
Demyelinating Diseases
/ genetics
Disease Models, Animal
Early Growth Response Protein 2
/ metabolism
Electrophysiological Phenomena
Ganglia, Spinal
/ metabolism
Gene Expression
Lipid Metabolism
Mice
Mice, Transgenic
Myelin Sheath
/ metabolism
Neuregulin-1
/ genetics
Schwann Cells
/ metabolism
Signal Transduction
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
29
08
2018
revised:
30
10
2018
accepted:
22
11
2018
pubmed:
28
11
2018
medline:
10
3
2020
entrez:
28
11
2018
Statut:
ppublish
Résumé
Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17), also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.
Identifiants
pubmed: 30481294
pii: 5210922
doi: 10.1093/hmg/ddy411
pmc: PMC6400047
doi:
Substances chimiques
Early Growth Response Protein 2
0
Neuregulin-1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
992-1006Informations de copyright
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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