Enhanced Axonal Neuregulin-1 Type-III Signaling Ameliorates Neurophysiology and Hypomyelination in a Charcot-Marie-Tooth Type 1B Mouse Model

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2018 Nov 28

PMID 30481294

Citations 23

Authors

Cristina Scapin

Cinzia Ferri

Emanuela Pettinato

Desiree Zambroni

Francesca Bianchi

Ubaldo Del Carro

Sophie Belin

Donatella Caruso

Nico Mitro

Marta Pellegatta

Carla Taveggia

Markus H Schwab

Klaus-Armin Nave

M Laura Feltri

Lawrence Wrabetz

Maurizio DAntonio

Affiliations

Soon will be listed here.

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.

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References

Yum S, Kleopa K, Shumas S, Scherer S . Diverse trafficking abnormalities of connexin32 mutants causing CMTX. Neurobiol Dis. 2002; 11(1):43-52. DOI: 10.1006/nbdi.2002.0545. View

Sanmaneechai O, Feely S, Scherer S, Herrmann D, Burns J, Muntoni F . Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain. 2015; 138(Pt 11):3180-92. PMC: 4643641. DOI: 10.1093/brain/awv241. View

Taveggia C, Zanazzi G, Petrylak A, Yano H, Rosenbluth J, Einheber S . Neuregulin-1 type III determines the ensheathment fate of axons. Neuron. 2005; 47(5):681-94. PMC: 2387056. DOI: 10.1016/j.neuron.2005.08.017. View

Maurel P, Salzer J . Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity. J Neurosci. 2000; 20(12):4635-45. PMC: 6772460. View

DAntonio M, Musner N, Scapin C, Ungaro D, Del Carro U, Ron D . Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. J Exp Med. 2013; 210(4):821-38. PMC: 3620355. DOI: 10.1084/jem.20122005. View

Nave K . Myelination and support of axonal integrity by glia. Nature. 2010; 468(7321):244-52. DOI: 10.1038/nature09614. View

Willem M, Garratt A, Novak B, Citron M, Kaufmann S, Rittger A . Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006; 314(5799):664-6. DOI: 10.1126/science.1132341. View

Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H . Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J Neurosci. 2004; 24(30):6724-32. PMC: 6729716. DOI: 10.1523/JNEUROSCI.5520-03.2004. View

Chrast R, Saher G, Nave K, Verheijen M . Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res. 2010; 52(3):419-34. PMC: 3035679. DOI: 10.1194/jlr.R009761. View

10.

Fledrich R, Stassart R, Klink A, Rasch L, Prukop T, Haag L . Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A. Nat Med. 2014; 20(9):1055-61. DOI: 10.1038/nm.3664. View

11.

Wrabetz L, DAntonio M, Pennuto M, Dati G, Tinelli E, Fratta P . Different intracellular pathomechanisms produce diverse Myelin Protein Zero neuropathies in transgenic mice. J Neurosci. 2006; 26(8):2358-68. PMC: 6674823. DOI: 10.1523/JNEUROSCI.3819-05.2006. View

12.

Wrabetz L, Feltri M, Quattrini A, Imperiale D, Previtali S, DAntonio M . P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J Cell Biol. 2000; 148(5):1021-34. PMC: 2174542. DOI: 10.1083/jcb.148.5.1021. View

13.

Feltri M, DAntonio M, Quattrini A, Numerato R, Arona M, Previtali S . A novel P0 glycoprotein transgene activates expression of lacZ in myelin-forming Schwann cells. Eur J Neurosci. 1999; 11(5):1577-86. DOI: 10.1046/j.1460-9568.1999.00568.x. View

14.

Siegel D . The modified stalk mechanism of lamellar/inverted phase transitions and its implications for membrane fusion. Biophys J. 1999; 76(1 Pt 1):291-313. PMC: 1302519. DOI: 10.1016/S0006-3495(99)77197-3. View

15.

Zenker J, Stettner M, Ruskamo S, Domenech-Estevez E, Baloui H, Medard J . A role of peripheral myelin protein 2 in lipid homeostasis of myelinating Schwann cells. Glia. 2014; 62(9):1502-12. DOI: 10.1002/glia.22696. View

16.

Deschenes S, Walcott J, Wexler T, Scherer S, Fischbeck K . Altered trafficking of mutant connexin32. J Neurosci. 1997; 17(23):9077-84. PMC: 6573613. View

17.

Cermenati G, Abbiati F, Cermenati S, Brioschi E, Volonterio A, Cavaletti G . Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation. J Lipid Res. 2011; 53(2):300-10. PMC: 3269154. DOI: 10.1194/jlr.M021188. View

18.

Ferri C, Quattrini A, DAntonio M . Electron Microscopy for the Analysis of Peripheral Nerve Myelin. Methods Mol Biol. 2018; 1791:3-13. DOI: 10.1007/978-1-4939-7862-5_1. View

19.

Majava V, Polverini E, Mazzini A, Nanekar R, Knoll W, Peters J . Structural and functional characterization of human peripheral nervous system myelin protein P2. PLoS One. 2010; 5(4):e10300. PMC: 2858655. DOI: 10.1371/journal.pone.0010300. View

20.

Quattrini A, Previtali S, Feltri M, Canal N, Nemni R, Wrabetz L . Beta 4 integrin and other Schwann cell markers in axonal neuropathy. Glia. 1996; 17(4):294-306. DOI: 10.1002/(SICI)1098-1136(199608)17:4<294::AID-GLIA4>3.0.CO;2-#. View