Charcot-Marie-Tooth-1A (CMT1A) is the most prevalent inherited peripheral neuropathy and no curing treatment is available. Even though the genetic cause (a duplication of the myelin protein PMP22) is known since the 90th, the pathological mechanisms are poorly understood. Clinically, affected patients suffer from muscular atrophies, foot deformities and sensory deficits. Histologically, diseased peripheral nerves show primary myelin abnormalities during development followed by a slowly progressing demyelination and subsequent axonal loss in adulthood, which accounts for clinical symptoms. Most specifically, CMT1A nerves exhibit onion bulb formations, which are supernumerary Schwann cells, wrapping concentrically around a central axon-Schwann cell unit.
Here, we show that Schwann cells of various demyelinating neuropathies express the paracrine growth factor Neuregulin-1 type-I, which is undetectable in healthy nerves but essential for regeneration after acute nerve injury. We could demonstrate a correlation of Nrg1-I expression in Schwann cells with clinical and histological disease hallmarks in various genetically modified mouse models.
Induction of glial Nrg1-I expression on a wildtype background induced symptoms reminiscent of a demyelinating neuropathy, whereas ablation of Nrg1 in Schwann cells of a CMT1A mouse model ameliorated neuropathological hallmarks. Especially, formation of onion bulbs, the key hallmark of CMT1A, could be attributed to Nrg1-I expression in Schwann cells. Furthermore, we showed that this is facilitated via the ErbB2/MEK/ERK signaling cascade.
This study proposes a model in which the beneficial, transient upregulation of glial Nrg1-I after acute nerve injury turns into a detrimental constantly active repair-response, due to functional loss of axonal contact in CMT1A and supposedly in other demyelinating neuropathies. This putative common pathway in peripheral neuropathies might open up promising new therapeutic strategies that interfere with the Nrg/ErbB2/MEK/ERK pathway, especially since ErbB2 receptor inhibitors are already applied in breast cancer therapies.:Abbreviations ........................................................................................................................................... i
1 Introduction ..................................................................................................................................... 1
1.1 The central and peripheral nervous system .............................................................................1
1.2 Schwann cells and Myelination ................................................................................................3
1.3 Neuregulin ................................................................................................................................6
1.4 Acute injury of the peripheral nervous system and Wallerian degeneration ....................... 11
1.5 Diseases of the peripheral nervous system: Neuropathies ................................................... 12
1.6 Charcot-Marie-Tooth disease ................................................................................................ 13
2 Aims ............................................................................................................................................... 16
3 Material and methods ................................................................................................................... 17
3.1 Animal models ....................................................................................................................... 17
3.2 Genotyping ............................................................................................................................ 18
3.3 Phenotyping tests .................................................................................................................. 18
3.4 Histology ................................................................................................................................ 19
3.5 Molecular biology .................................................................................................................. 22
3.6 Material ................................................................................................................................. 26
4 Results ........................................................................................................................................... 29
4.1 Ablation of glial Neuregulin-1 improves the clinical phenotype in a mouse model of CMT1A ………………………………………………………………………………………………………………………………………… 29
4.2 Overexpression of Neuregulin-1 type-I induces hallmarks of peripheral neuropathy ......... 34
4.3 Glial Neuregulin-1 type-I signaling promotes survival and attraction of Schwann cells ....... 36
4.4 Dedifferentiation promoting signaling pathways are induced by SC-Nrg1-I ........................ 40
5 Discussion ...................................................................................................................................... 45
6 Abstract ......................................................................................................................................... 50
7 Zusammenfassung ......................................................................................................................... 51
8 References ..................................................................................................................................... 52
9 Appendix .......................................................................................................................................... iii
9.1 List of figures ........................................................................................................................... iii
9.2 List of tables............................................................................................................................. iv
9.3 Erklärung über die eigenständige Abfassung der Arbeit .......................................................... v
Content
9.5 Publications ........................................................................................................................... viii
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:78021 |
| Date | 11 February 2022 |
| Creators | Akkermann, Dagmar |
| Contributors | Stassart, Ruth, Morawski, Markus, Hirrlinger, Johannes, Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
Page generated in 0.0786 seconds