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

Nazanin Ghazanfari, Sofie Trajanovska, Marco Morsch, Simon X. Liang, Stephen W. Reddel, William D. Phillips*

*Corresponding author for this work

    Research output: Contribution to journalReview articlepeer-review

    6 Citations (Scopus)

    Abstract

    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 IgGfromanti-MuSK+ myasthenia gravis patients developedmuscle 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.

    Original languageEnglish
    Pages (from-to)54-61
    Number of pages8
    JournalAnnals of the New York Academy of Sciences
    Volume1412
    Issue number1
    DOIs
    Publication statusPublished - Jan 2018

    Keywords

    • Mouse models
    • Muscle-specific kinase
    • Myasthenia gravis
    • Neuromuscular disease
    • Neuromuscular junction

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