NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies

Robert Fledrich (), Dagmar Akkermann, Vlad Schütza, Tamer A. Abdelaal, Doris Hermes, Erik Schäffner, M. Clara Soto-Bernardini, Tilmann Götze, Axel Klink, Kathrin Kusch, Martin Krueger, Theresa Kungl, Clara Frydrychowicz, Wiebke Möbius, Wolfgang Brück, Wolf C. Mueller, Ingo Bechmann, Michael W. Sereda, Markus H. Schwab (), Klaus-Armin Nave () and Ruth M. Stassart ()
Additional contact information
Robert Fledrich: University of Leipzig
Dagmar Akkermann: Max-Planck-Institute of Experimental Medicine
Vlad Schütza: Max-Planck-Institute of Experimental Medicine
Tamer A. Abdelaal: Max-Planck-Institute of Experimental Medicine
Doris Hermes: Max-Planck-Institute of Experimental Medicine
Erik Schäffner: Max-Planck-Institute of Experimental Medicine
M. Clara Soto-Bernardini: Max-Planck-Institute of Experimental Medicine
Tilmann Götze: Max-Planck-Institute of Experimental Medicine
Axel Klink: Max-Planck-Institute of Experimental Medicine
Kathrin Kusch: Max-Planck-Institute of Experimental Medicine
Martin Krueger: University of Leipzig
Theresa Kungl: Max-Planck-Institute of Experimental Medicine
Clara Frydrychowicz: University Hospital Leipzig
Wiebke Möbius: Max-Planck-Institute of Experimental Medicine
Wolfgang Brück: University Medical Center Göttingen
Wolf C. Mueller: University Hospital Leipzig
Ingo Bechmann: University of Leipzig
Michael W. Sereda: Max-Planck-Institute of Experimental Medicine
Markus H. Schwab: Max-Planck-Institute of Experimental Medicine
Klaus-Armin Nave: Max-Planck-Institute of Experimental Medicine
Ruth M. Stassart: Max-Planck-Institute of Experimental Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells induce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental.

Date: 2019
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DOI: 10.1038/s41467-019-09385-6

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