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- Title
Enhanced axonal neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot–Marie–Tooth type 1B mouse model.
- Authors
Scapin, Cristina; Ferri, Cinzia; Pettinato, Emanuela; Zambroni, Desiree; Bianchi, Francesca; Carro, Ubaldo Del; Belin, Sophie; Caruso, Donatella; Mitro, Nico; Pellegatta, Marta; Taveggia, Carla; Schwab, Markus H; Nave, Klaus-Armin; Feltri, M Laura; Wrabetz, Lawrence; D'Antonio, Maurizio
- 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.
- Publication
Human Molecular Genetics, 2019, Vol 28, Issue 6, p992
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddy411