The mouse passive‐transfer model of MuSK myasthenia gravis: disrupted MuSK signaling causes synapse failure

While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle‐specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscul...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2018-01, Vol.1412 (1), p.54-61
Main Authors: Ghazanfari, Nazanin, Trajanovska, Sofie, Morsch, Marco, Liang, Simon X., Reddel, Stephen W., Phillips, William D.
Format: Article
Language:English
Subjects:
Acetylcholine receptors
Antibodies
Autoantibodies
Cholinesterase
Cholinesterase inhibitors
Immunoglobulin G
Kinases
mouse models
Muscles
muscle‐specific kinase
MUSK protein
Myasthenia gravis
neuromuscular disease
neuromuscular junction
Neuromuscular junctions
Neuromuscular transmission
Patients
Phosphorylation
Protein-tyrosine kinase
Proteins
Pyridostigmine
Receptors
Rodents
Signaling
Synapses
Tyrosine
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Summary:While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle‐specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscular junction. During development, MuSK serves as a signaling hub, coordinating the alignment of the pre‐ and postsynaptic components of the synapse. Adult mice that received repeated daily injections of IgG from anti‐MuSK+ myasthenia gravis patients developed muscle weakness, associated with neuromuscular transmission failure. MuSK autoantibodies are predominantly of the IgG4 type. They suppress the kinase activity of MuSK and the phosphorylation of target proteins in the postsynaptic membrane. Loss of postsynaptic acetylcholine receptors is the primary cause of neuromuscular transmission failure. MuSK autoantibodies also disrupt the capacity of the motor nerve terminal to adaptively increase acetylcholine release in response to the reduced postsynaptic responsiveness to acetylcholine. The passive IgG transfer model of MuSK myasthenia gravis has been used to test candidate treatments. Pyridostigmine, a first‐line cholinesterase inhibitor drug, exacerbated the disease process, while 3,4‐diaminopyridine and albuterol were found to be beneficial in this mouse model.
ISSN:0077-8923
1749-6632
DOI:10.1111/nyas.13513