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  Enhanced axonal Neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot-Marie-Tooth type 1B mouse model

Scapin, C., Ferri, C., Pettinato, E., Zambroni, D., Bianchi, F., Dell Carro, U., et al. (2019). Enhanced axonal Neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot-Marie-Tooth type 1B mouse model. Human Molecular Genetics, 28(6), 992-1006. doi:10.1093/hmg/ddy411.

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Scapin, Cristina, Autor
Ferri, Cinzia, Autor
Pettinato, Emanuela, Autor
Zambroni, Desiree, Autor
Bianchi, Francesca, Autor
Dell Carro, Ubaldo, Autor
Belin, Sophie, Autor
Caruso, Donatella, Autor
Mitro, Nico, Autor
Pellegatta, Marta, Autor
Taveggia, Carla, Autor
Schwab, Markus H.1, Autor           
Nave, Klaus-Armin1, Autor           
Feltri, M. Laura, Autor
Wrabetz, Lawrence, Autor
D'Antonio, Maurizio , Autor
Affiliations:
1Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173664              

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 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2018-11-272019-03-15
 Publikationsstatus: Erschienen
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 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1093/hmg/ddy411
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Titel: Human Molecular Genetics
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Oxford, England : IRL Press
Seiten: - Band / Heft: 28 (6) Artikelnummer: - Start- / Endseite: 992 - 1006 Identifikator: ISSN: 0964-6906
CoNE: https://pure.mpg.de/cone/journals/resource/954925581153