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; Ruth M Stassart

doi:10.1038/s41467-019-09385-6

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

Nat Commun. 2019 Apr 1;10(1):1467. doi: 10.1038/s41467-019-09385-6.

Authors

Robert Fledrich^{1

2}, Dagmar Akkermann^{3

4}, Vlad Schütza^{3

4}, Tamer A Abdelaal^{3

4}, Doris Hermes^{3

5}, Erik Schäffner^{3

4}, M Clara Soto-Bernardini^{3

6}, Tilmann Götze^{3

7}, Axel Klink³, Kathrin Kusch³, Martin Krueger⁸, Theresa Kungl³, Clara Frydrychowicz⁴, Wiebke Möbius^{3

9}, Wolfgang Brück¹⁰, Wolf C Mueller⁴, Ingo Bechmann⁸, Michael W Sereda^{3

5}, Markus H Schwab^{11

12

13}, Klaus-Armin Nave¹⁴, Ruth M Stassart^{15

16}

Affiliations

¹ Institute of Anatomy, University of Leipzig, Liebigstr. 13, 04103, Leipzig, Germany. [email protected].
² Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany. [email protected].
³ Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.
⁴ Department of Neuropathology, University Hospital Leipzig, Liebigstr. 26, 04103, Leipzig, Germany.
⁵ Department of Clinical Neurophysiology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
⁶ Center for Research in Biotechnology (CIB), Costa Rican Institute of Technology (TEC), Cartago, Costa Rica.
⁷ Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625, Hanover, Germany.
⁸ Institute of Anatomy, University of Leipzig, Liebigstr. 13, 04103, Leipzig, Germany.
⁹ Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
¹⁰ Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
¹¹ Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany. [email protected].
¹² Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625, Hanover, Germany. [email protected].
¹³ Center for Systems Neuroscience (ZSN), Bünteweg 2, 30559, Hanover, Germany. [email protected].
¹⁴ Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany. [email protected].
¹⁵ Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany. [email protected].
¹⁶ Department of Neuropathology, University Hospital Leipzig, Liebigstr. 26, 04103, Leipzig, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Charcot-Marie-Tooth Disease / genetics
Charcot-Marie-Tooth Disease / metabolism
Charcot-Marie-Tooth Disease / pathology
Demyelinating Diseases / genetics*
Demyelinating Diseases / metabolism
Demyelinating Diseases / pathology
Diabetes Mellitus, Type 1 / complications
Diabetic Neuropathies / etiology
Diabetic Neuropathies / genetics
Diabetic Neuropathies / metabolism
Diabetic Neuropathies / pathology
Humans
MAP Kinase Signaling System
Mice
Mice, Transgenic
Microscopy, Electron
Motor Activity
Myelin Proteins / genetics
Neuregulin-1 / genetics*
Neuregulin-1 / metabolism
Neuritis, Autoimmune, Experimental / genetics
Neuritis, Autoimmune, Experimental / metabolism
Neuritis, Autoimmune, Experimental / pathology
Neuroglia / metabolism
Paracrine Communication*
Rats
Receptor, ErbB-2 / metabolism
Schwann Cells / metabolism*
Schwann Cells / ultrastructure
Sciatic Nerve / injuries
Signal Transduction
Sural Nerve / metabolism*
Sural Nerve / ultrastructure
Tibial Nerve

Substances

Myelin Proteins
NRG1 protein, human
Neuregulin-1
Nrg1 protein, mouse
Nrg1 protein, rat
PMP22 protein, human
Erbb2 protein, mouse
Receptor, ErbB-2