Glial ErbB2-receptor inhibition as a novel therapeutic rational for Charcot-Marie-Tooth disease 1A (CMT1A).
Final Report Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy, and affected patients suffer from a progressive muscle weakness and sensory impairments. The underlying genetic alteration primarily affects Schwann cells, the glial cells of the peripheral nervous system. Among others, diseased Schwann cells are characterized by a persistent overexpression of the growth factor Neuregulin-1 (NRG1). Excessive NRG1 production induces morphological and molecular changes in Schwann cells, ultimately exacerbating disease severity. Previous studies demonstrated that deleting the Nrg1 gene from Schwann cells in a CMT1A mouse model reduces the overactivation of ErbB2 receptors and the downstream MEK/ERK signaling cascade, alleviating typical disease symptoms. Based on these findings, we hypothesized that an inhibition of the overactive ErbB2/MEK/ERK signaling pathway could represent a potential therapeutic strategy for CMT1A. The present project hence aimed at investigating the impact of a targeted inhibition of the ErbB2/MEK/ERK signaling pathway in Schwann cells on CMT1A pathology. Two approaches were employed: genetic manipulations in mice to better understand the pathomechanistic consequences of ErbB2 activation in CMT1A and the use of clinically available drugs to directly block the ErbB2/MEK/ERK pathway and to assess their therapeutic efficacy. In the first experimental study, genetic ablation of ErbB2 in Schwann cells of CMT1A mice did not lead to significant improvements in phenotypic, electrophysiological, or histological parameters. On the contrary, it was associated with worsening electrophysiological outcomes and an increased number of hypomyelinated axons. Similarly, pharmacological treatments with Herceptin and Selumetinib did not yield significant therapeutic benefits for CMT1A pathology. Instead, both compounds tended to exacerbate disease pathology at both functional and histological levels. These findings necessitate a revision of the initial hypothesis and raise the question of what role ErbB/MEK/ERK pathway activation, independent of glial NRG1 function, might play in CMT1A disease. One possible explanation is an axon-mediated activation of the ErbB2/MEK/ERK signaling cascade, which may be required to counteract disease progression by promoting remyelination or slowing demyelination. In conclusion, our findings highlight the complexity of NRG1/ErbB/MEK/ERK signaling in CMT1A pathogenesis and provide key insights for the development of new therapeutic approaches.
Publications
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Neuregulin-1 signaling in repair responses of peripheral nerve diseases, XV European Meeting on Glial Cells in Health and Disease 2021
Stassart R.M.
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Myelin heterogeneity in the peripheral nerve axons, Oral presentation at the Annual Meeting of the Peripheral Nerve Society, 2023
Stassart R.M.
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Repair strategies of diseases of the peripheral nervous system. Oral presentation at the International Society Meeting of Neuropathology (ICN), 2023
Stassart R.M.
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Pathophysiology of demyelinating Neuropathies. Oral presentation at the 5th Neuromuscular Joint Meeting of the Belgian-Dutch Neuromuscular Study Club and of the German Reference Center for Neuromuscular Diseases of the DGNN in Vaals, The Netherlands, 2024
Stassart R.M.
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Schwann Cells as Orchestrators of Nerve Repair: Implications for Tissue Regeneration and Pathologies. Cold Spring Harbor Perspectives in Biology, 16(6), a041363.
Stassart, Ruth M.; Gomez-Sanchez, Jose A. & Lloyd, Alison C.
