| Title: |
MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis |
| Authors: |
Halliez, Marius; Cottin, Steve; You, Axel; Buon, Céline; Grondin, Antony; Lippens, Léa, S; Lemaitre, Mégane; Ezan, Jérome; Isch, Charlotte; Rufin, Yann; Montcouquiol, Mireille; Sans, Nathalie; Fontaine, Bertrand; Messéant, Julien; Le Panse, Rozen; Strochlic, Laure |
| Contributors: |
Centre de recherche en Myologie – U974 SU-INSERM; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); ANR-22-CE13-0031,MODCOM,Modulation de la communication trans-synaptique à la jonction neuromusculaire: des voies de signalisation aux approches thérapuetiques(2022) |
| Source: |
ISSN: 1558-8238 ; The Journal of clinical investigation ; https://hal.science/hal-05344474 ; The Journal of clinical investigation, 2025, 135, ⟨10.1172/jci173308⟩. |
| Publisher Information: |
CCSD; American Society for Clinical Investigation |
| Publication Year: |
2025 |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
International audience ; The neuromuscular junction (NMJ), a synapse between the motor neuron terminal and a skeletal muscle fiber, is crucial throughout life in maintaining the reliable neurotransmission required for functional motricity. Disruption of this system leads to neuromuscular disorders, such as autoimmune myasthenia gravis (MG), the most common form of NMJ disease. MG is caused by autoantibodies directed mostly against the acetylcholine receptor (AChR) or the muscle-specific kinase MuSK. Several studies report immunoreactivity to the Frizzled-like cysteine-rich Wnt-binding domain of MuSK (CRD) in patients, although the pathogenicity of the antibodies involved remains unknown. We showed here that the immunoreactivity to MuSK CRD induced by the passive transfer of anti-MuSK CRD antibodies in mice led to typical MG symptoms, characterized by a loss of body weight and a locomotor deficit. The functional and morphological integrity of the NMJ was compromised with a progressive decay of neurotransmission and disruption of the structure of presynaptic and postsynaptic compartments. We found that anti-MuSK CRD antibodies completely abolished Agrin-mediated AChR clustering by decreasing the Lrp4-MuSK interaction. These results demonstrate the role of the MuSK CRD in MG pathogenesis and improve our understanding of the underlying pathophysiological mechanisms. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1172/jci173308 |
| Availability: |
https://hal.science/hal-05344474; https://hal.science/hal-05344474v1/document; https://hal.science/hal-05344474v1/file/Halliez%20et%20al.pdf; https://doi.org/10.1172/jci173308 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.770B44A3 |
| Database: |
BASE |