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

Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S. Lippens, Megane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic
Journal of Clinical Investigation. 2025-06-12; :
DOI: 10.1172/jci173308

PubMed

Lire sur PubMed

https://www.bordeaux-neurocampus.fr/11791

Halliez M(1), Cottin S(1), You A(1), Buon C(1), Grondin A(1), Lippens LS(1),
Lemaitre M(2), Ezan J(3), Isch C(3), Rufin Y(4), Montcouquiol M(3), Sans N(3),
Fontaine B(1), Messéant J(1), Le Panse R(1), Strochlic L(1).

Author information:
(1)UMR-S 974 Centre de Recherche en Myologie, Sorbonne Université, Institut
National de la Santé et de la Recherche Médicale, Institut de Myologie, Paris,
France.
(2)UMS28 Phénotypage du Petit Animal, Sorbonne Université, Institut National de
la Santé et de la Recherche Médicale, Paris, France.
(3)Neurocentre Magendie, Université Bordeaux, Institut National de la Santé et
de la Recherche Médicale, Bordeaux, France.
(4)Biochemistry and Biophysics Facility of the Bordeaux Neurocampus (BioProt),
Bordeaux, France.

The neuromuscular junction (NMJ), 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 auto-immune myasthenia gravis (MG),
the most common form of NMJ diseases. 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
pre- and post-synaptic compartments. We found that anti-MuSKCRD antibodies
completely abolished Agrin-mediated AChR clustering by decreasing the Lrp4-MuSK
interaction. These results provide the first demonstration of the role of the
MuSK CRD in MG pathogenesis and improve our understanding of the underlying
pathophysiological mechanisms.