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Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A

Nature Medicine volume 20, pages 1055–1061 (2014)Cite this article

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Abstract

Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A)1,2,3, a disease without a known cure4,5,6. Although demyelination represents a characteristic feature, the clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation4,7. CMT1A disease manifests within the first two decades of life8,9, and walking disabilities, foot deformities and electrophysiological abnormalities are already present in childhood7,8,9,10,11. Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.

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Figure 1: Pmp22-transgenic Schwann cells acquire a differentiation defect during early postnatal development that is sustained until adulthood.
Figure 2: Activation of the Akt signaling pathway counteracts the perturbed differentiation in Pmp22-transgenic Schwann cells.
Figure 3: Nrg1(I) transgenic overexpression improves CMT1A disease in PMP22-transgenic mice.
Figure 4: Treatment of CMT rats with exogeneous rhNRG1 during early postnatal development induces a long-term improvement of the disease.

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References

  1. Sereda, M. et al. A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 16, 1049–1060 (1996).

    Article  CAS  Google Scholar 

  2. Lupski, J.R. et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).

    Article  CAS  Google Scholar 

  3. Raeymaekers, P. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). Neuromuscul. Disord. 1, 93–97 (1991).

    Article  CAS  Google Scholar 

  4. Pareyson, D. & Marchesi, C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 8, 654–667 (2009).

    Article  CAS  Google Scholar 

  5. Fledrich, R., Stassart, R.M. & Sereda, M.W. Murine therapeutic models for Charcot-Marie-Tooth (CMT) disease. Br. Med. Bull. 102, 89–113 (2012).

    Article  CAS  Google Scholar 

  6. Patzkó, A. & Shy, M.E. Update on Charcot-Marie-Tooth disease. Curr. Neurol. Neurosci. Rep. 11, 78–88 (2011).

    Article  Google Scholar 

  7. Berciano, J., García, A., Calleja, J. & Combarros, O. Clinico-electrophysiological correlation of extensor digitorum brevis muscle atrophy in children with Charcot-Marie-Tooth disease 1A duplication. Neuromuscul. Disord. 10, 419–424 (2000).

    Article  CAS  Google Scholar 

  8. Harding, A.E. & Thomas, P.K. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103, 259–280 (1980).

    Article  CAS  Google Scholar 

  9. Thomas, P.K. et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 120, 465–478 (1997).

    Article  Google Scholar 

  10. Burns, J., Ryan, M.M. & Ouvrier, R.A. Evolution of foot and ankle manifestations in children with CMT1A. Muscle Nerve 39, 158–166 (2009).

    Article  Google Scholar 

  11. Yiu, E.M., Burns, J., Ryan, M.M. & Ouvrier, R.A. Neurophysiologic abnormalities in children with Charcot-Marie-Tooth disease type 1A. J. Peripher. Nerv. Syst. 13, 236–241 (2008).

    Article  Google Scholar 

  12. Fledrich, R. et al. A rat model of Charcot-Marie-Tooth disease 1A recapitulates disease variability and supplies biomarkers of axonal loss in patients. Brain 135, 72–87 (2012).

    Article  Google Scholar 

  13. Sereda, M.W., Meyer zu Hörste, G., Suter, U., Uzma, N. & Nave, K.-A. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT–1A). Nat. Med. 9, 1533–1537 (2003).

    Article  CAS  Google Scholar 

  14. Gabreëls-Festen, A.A. et al. Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations. Acta Neuropathol. 90, 645–649 (1995).

    Article  Google Scholar 

  15. Kobsar, I., Hasenpusch–Theil, K., Wessig, C., Müller, H.W. & Martini, R. Evidence for macrophage-mediated myelin disruption in an animal model for Charcot-Marie-Tooth neuropathy type 1A. J. Neurosci. Res. 81, 857–864 (2005).

    Article  CAS  Google Scholar 

  16. Jessen, K.R. & Mirsky, R. The origin and development of glial cells in peripheral nerves. Nat. Rev. Neurosci. 6, 671–682 (2005).

    Article  CAS  Google Scholar 

  17. Hanemann, C.O., Gabreëls–Festen, A.A.W.M., Stoll, G. & Müller, H.W. Schwann cell differentiation in Charcot-Marie-Tooth disease type 1A (CMT1A): normal number of myelinating Schwann cells in young CMT1A patients and neural cell adhesion molecule expression in onion bulbs. Acta Neuropathol. 94, 310–315 (1997).

    Article  CAS  Google Scholar 

  18. Hanemann, C.O., Gabreëls–Fasten, A.A.W.M., Müller, H.W. & Stoll, G. Low affinity NGF receptor expression in CMT1A nerve biopsies of different disease stages. Brain 119, 1461–1469 (1996).

    Article  Google Scholar 

  19. Adlkofer, K. et al. Hypermyelination and demyelianting peripheral neuropathy in Pmp22-deficient mice. Nat. Genet. 11, 274–280 (1995).

    Article  CAS  Google Scholar 

  20. Martini, R., Klein, D. & Groh, J. Similarities between inherited demyelinating neuropathies and Wallerian degeneration: an old repair program may cause myelin and axon perturbation under nonlesion conditions. Am. J. Pathol. 183, 655–660 (2013).

    Article  CAS  Google Scholar 

  21. Fischer, S., Weishaupt, A., Troppmair, J. & Martini, R. Increase of MCP-1 (CCL2) in myelin mutant Schwann cells is mediated by Mek-Erk signaling pathway. Glia 56, 836–843 (2008).

    Article  Google Scholar 

  22. Kohl, B., Fischer, S., Groh, J., Wessig, C. & Martini, R. MCP-1/CCL2 modifies axon properties in a PMP22-overexpressing mouse model for Charcot-Marie-Tooth 1A neuropathy. Am. J. Pathol. 176, 1390–1399 (2010).

    Article  CAS  Google Scholar 

  23. Napoli, I. et al. A central role for the Erk-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73, 729–742 (2012).

    Article  CAS  Google Scholar 

  24. Mendoza, M.C., Emrah Er, E. & Blenis, J. The Ras-Erk and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem. Sci. 36, 320–328 (2011).

    Article  CAS  Google Scholar 

  25. Nobbio, L. et al. Impairment of PMP22 transgenic Schwann cells differentiation in culture: implications for Charcot-Marie-Tooth type 1A disease. Neurobiol. Dis. 16, 263–273 (2004).

    Article  CAS  Google Scholar 

  26. Syed, N. et al. Soluble neuregulin-1 has bifunctional, concentration-dependent effects on Schwann cell myelination. J. Neurosci. 30, 6122–6131 (2010).

    Article  CAS  Google Scholar 

  27. Taveggia, C. et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).

    Article  CAS  Google Scholar 

  28. Birchmeier, C. & Nave, K.-A. Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia 56, 1491–1497 (2008).

    Article  Google Scholar 

  29. Michailov, G.V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

    Article  CAS  Google Scholar 

  30. Falls, D.L. Neuregulins and the neuromuscular system: 10 years of answers and questions. J. Neurocytol. 32, 619–647 (2003).

    Article  CAS  Google Scholar 

  31. Stassart, R.M. et al. A role for Schwann cell–derived neuregulin-1 in remyelination. Nat. Neurosci. 16, 48–54 (2013).

    Article  CAS  Google Scholar 

  32. Mendes–Ferreira, P., De Keulenaer, G.W., Leite–Moreira, A.F. & Brás–Silva, C. Therapeutic potential of neuregulin-1 in cardiovascular disease. Drug Discov. Today 18, 836–842 (2013).

    Article  Google Scholar 

  33. Huxley, C. et al. Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice. Hum. Mol. Genet. 7, 449–458 (1998).

    Article  CAS  Google Scholar 

  34. Bersell, K., Arab, S., Haring, B. & Kühn, B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138, 257–270 (2009).

    Article  CAS  Google Scholar 

  35. Kato, T. et al. Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia. Mol. Psychiatry 16, 307–320 (2011).

    Article  CAS  Google Scholar 

  36. Haney, C. et al. Ultrastructural distribution of PMP22 in Charcot-Marie-Tooth disease type 1A. J. Neuropathol. Exp. Neurol. 55, 290–299 (1996).

    Article  CAS  Google Scholar 

  37. Koike, H. et al. Nonmyelinating Schwann cell involvement with well-preserved unmyelinated axons in Charcot-Marie-Tooth disease type 1A. J. Neuropathol. Exp. Neurol. 66, 1027–1036 (2007).

    Article  CAS  Google Scholar 

  38. Arthur–Farraj, P.J. et al. c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 75, 633–647 (2012).

    Article  Google Scholar 

  39. D'Antonio, M. et al. Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. J. Exp. Med. 210, 821–838 (2013).

    Article  CAS  Google Scholar 

  40. Patzkó, A. et al. Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice. Brain 135, 3551–3566 (2012).

    Article  Google Scholar 

  41. Meyer zu Hörste, G. et al. Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy. Ann. Neurol. 61, 61–72 (2007).

    Article  Google Scholar 

  42. Brockes, J.P. et al. Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Res. 165, 105–118 (1979).

    Article  CAS  Google Scholar 

  43. Krishnan, A.V., Lin, C.S.-Y., Park, S.B. & Kiernan, M.C. Axonal ion channels from bench to bedside: a translational neuroscience perspective. Prog. Neurobiol. 89, 288–313 (2009).

    Article  CAS  Google Scholar 

  44. Nodera, H. et al. Nerve excitability properties in Charcot-Marie-Tooth disease type 1A. Brain 127, 203–211 (2004).

    Article  Google Scholar 

  45. Boërio, D., Greensmith, L. & Bostock, H. Excitability properties of motor axons in the maturing mouse. J. Peripher. Nerv. Syst. 14, 45–53 (2009).

    Article  Google Scholar 

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Acknowledgements

We thank U. Suter (Eidgenössische Technische Hochschule Zurich) for providing Pmp22-deficient mice and C. Huxley (Imperial College School of Medicine, London) for providing Pmp22-transgenic mice. We are grateful to T. Durkaya, C. Maack, A. Fahrenholz, T. Freerck, M. Wehe and A. Wohltmann for technical support. We thank W. Möbius and T. Ruhwedel for help with electron microscopy. This work was supported by grants of the German Research Foundation (DFG) Research Center Molecular Physiology of the Brain, European Commission FP7-201535 (Neuron-Glia Interactions in Nerve Development and Disease) to K.-A.N. M.W.S. and R.F. were supported by the German Ministry of Education and Research (BMBF, FKZ 01ES0812 to M.W.S.). M.W.S. was also supported by the Association Francaise contre les Myopathies (NR 15037) and holds a Heisenberg Professorship granted by the DFG (GZ: SE 1944/1-1). K.-A.N. holds a European Research Council Advanced Investigator Grant.

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  1. Robert Fledrich and Ruth M Stassart: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    Robert Fledrich, Ruth M Stassart, Axel Klink, Lennart M Rasch, Thomas Prukop, Theresa Kungl, Tamer A M Abdelaal, Naureen Keric, Klaus-Armin Nave & Michael W Sereda

  2. Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany

    Ruth M Stassart, Christine Stadelmann & Wolfgang Brück

  3. Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany

    Thomas Prukop

  4. Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany

    Lauren Haag, Dirk Czesnik & Michael W Sereda

  5. Department of Neurosurgery, University Medical Center, Johannes–Gutenberg University of Mainz, Mainz, Germany

    Naureen Keric

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Contributions

R.F. and R.M.S. designed the study, performed experiments and wrote the manuscript. A.K., T.P., L.M.R., T.K., T.A.M.A. and N.K. contributed to experiments. L.H. and D.C. performed threshold electrotonus measurements. C.S. and W.B. contributed to immunohistochemistry and discussions. M.W.S. and K.-A.N. contributed to the manuscript and supervised the project.

Corresponding authors

Correspondence to Ruth M Stassart, Klaus-Armin Nave or Michael W Sereda.

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Fledrich, R., Stassart, R., Klink, A. et al. Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A. Nat Med 20, 1055–1061 (2014). https://doi.org/10.1038/nm.3664

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