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

Scapin, Cristina; Ferri, Cinzia; Pettinato, Emanuela; Zambroni, Desiree; Bianchi, Francesca; Dell Carro, Ubaldo; Belin, Sophie; Caruso, Donatella; Mitro, Nico; Pellegatta, Marta; Taveggia, Carla; Schwab, Markus H.; Nave, Klaus-Armin; Feltri, M. Laura; Wrabetz, Lawrence; D'Antonio, Maurizio

doi:10.1093/hmg/ddy411

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

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Schwab, Markus H.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Nave, Klaus-Armin
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0002-9762-5

Abstract

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.