Myasthenia gravis (MG) is caused by autoantibodies directed mainly against the acetylcholine receptor (AChR) or the MuSK receptor tyrosine kinase located at the neuromuscular junction. Several studies have reported immunoreactivity against the Frizzled cysteine-rich domain (CRD) of MuSK in patients, although the pathogenicity of the antibodies involved remains unknown.
A collaboration involving several teams from the Institute’s Research Centre has shown that :
- immunoreactivity against the CRD domain of MuSK, induced by passive transfer of anti-MuSKCRD antibodies in mice, leads to symptoms typical of MG (loss of body weight and locomotor deficits)
- the functional and morphological integrity of the JNM is compromised, leading to a progressive decrease in neurotransmission and disruption of the structure of the pre- and post-synaptic compartments.
- anti-MuSKCRD antibodies completely abolish agrin-mediated RACh aggregation by reducing Lrp4-MuSK interaction.
These results demonstrate for the first time the role of the CRD domain of MuSK in the pathogenesis of MG and improve our understanding of the underlying pathophysiological mechanisms.
