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Ann N Y Acad Sci. 2018 Jan;1412(1):54-61. doi: 10.1111/nyas.13513. Epub 2017 Nov 10.

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

Author information

  • 1Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
  • 2Department of Biomedical Sciences, Macquarie University, Sydney, New South Wales, Australia.
  • 3Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Liaoning Medical University, Jinzhou, China.
  • 4Department of Molecular Medicine, Concord Hospital, Sydney, New South Wales, Australia.

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 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.

KEYWORDS:

mouse models; muscle-specific kinase; myasthenia gravis; neuromuscular disease; neuromuscular junction

PMID:
29125188
DOI:
10.1111/nyas.13513
[PubMed - in process]

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