MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis
Marius Halliez, … , Rozen Le Panse, Laure Strochlic
Marius Halliez, … , Rozen Le Panse, Laure Strochlic
Published June 12, 2025
Citation Information: J Clin Invest. 2025;135(15):e173308. https://doi.org/10.1172/JCI173308.
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Research Article Immunology Muscle biology Neuroscience

MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis

Abstract

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-MuSKCRD 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-MuSKCRD 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.

Authors

Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S. Lippens, Mégane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic

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Figure 1

Anti-MuSKCRD antibody injections induce myasthenia-like symptoms in mice.

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Anti-MuSKCRD antibody injections induce myasthenia-like symptoms in mice...
(A and B) Lysates of COS7 cells transfected with a MuSK-HA construct (A) and C2C12 myotubes (B) were subjected to IP with control IgG or anti-MuSKCRD antibodies. Whole-lysate Western blots (Input) were performed to demonstrate the presence of the protein of interest. IB, immunoblot; GAPDH, loading control. (C) Schematic representation of the EAMG passive-transfer model protocol. PBS, control animals receiving injections of PBS; IgG, animals receiving injections of control IgG antibodies; CRD, animals receiving injections of anti-MuSKCRD antibodies. Black arrows indicate the days on which clinical tests were performed. (D) ELISA for total anti-MuSKCRD antibody dosing in serum from control (PBS and IgG) and immunized (CRD) animals (1:100,000) during the course of the protocol. (E) Representative images of PBS, IgG, and CRD animals running on a treadmill during the last clinical test session (day 19). (F) Body weight measurements for the PBS, IgG, and CRD groups during the course of the protocol. Weight was normalized relative to the value obtained during the preinjection clinical test (day –2). (G) Global clinical score (GCS) of PBS, IgG, and CRD animals during the protocol. GCS includes body weight, objective observation, hanging upside-down test, and grip test results. The data are shown as mean ± SEM. PBS, n = 8; IgG, n = 7; CRD, n = 8; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. For D, F, and G, black statistical symbols are PBS versus CRD; gray statistical symbols are IgG versus CRD; 2-way ANOVA with Tukey’s post hoc test (D, F, and G).