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

• Published in: Human molecular genetics Vol. 28; no. 6; pp. 992 - 1006
• Main Authors: Scapin, Cristina, Ferri, Cinzia, Pettinato, Emanuela, Zambroni, Desiree, Bianchi, Francesca, Del 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.03.2019
• Subjects: Animals; Axons - metabolism; Charcot-Marie-Tooth Disease - etiology; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - physiopathology; Demyelinating Diseases - genetics; Demyelinating Diseases - metabolism; 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; Neuregulin-1 - metabolism; Schwann Cells - metabolism; Signal Transduction
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddy411

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.