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Patient autoantibodies deplete postsynaptic muscle‐specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice
Author(s) -
Cole R. N.,
Ghazanfari N.,
Ngo S. T.,
Gervásio O. L.,
Reddel S. W.,
Phillips W. D.
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2010.190298
Subject(s) - postsynaptic potential , myasthenia gravis , neuromuscular junction , acetylcholine receptor , autoantibody , endocrinology , chemistry , medicine , biology , microbiology and biotechnology , receptor , neuroscience , antibody , biochemistry , immunology
The postsynaptic muscle‐specific kinase (MuSK) coordinates formation of the neuromuscular junction (NMJ) during embryonic development. Here we have studied the effects of MuSK autoantibodies upon the NMJ in adult mice. Daily injections of IgG from four MuSK autoantibody‐positive myasthenia gravis patients (MuSK IgG; 45 mg day −1 i.p. for 14 days) caused reductions in postsynaptic ACh receptor (AChR) packing as assessed by fluorescence resonance energy transfer (FRET). IgG from the patients with the highest titres of MuSK autoantibodies caused large (51–73%) reductions in postsynaptic MuSK staining (cf. control mice; P < 0.01) and muscle weakness. Among mice injected for 14 days with control and MuSK patient IgGs, the residual level of MuSK correlated with the degree of impairment of postsynaptic AChR packing. However, the loss of postsynaptic MuSK preceded this impairment of postsynaptic AChR. When added to cultured C2 muscle cells the MuSK autoantibodies caused tyrosine phosphorylation of MuSK and the AChR β‐subunit, and internalization of MuSK from the plasma membrane. The results suggest a pathogenic mechanism in which MuSK autoantibodies rapidly deplete MuSK from the postsynaptic membrane leading to progressive dispersal of postsynaptic AChRs. Moreover, maintenance of postsynaptic AChR packing at the adult NMJ would appear to depend upon physical engagement of MuSK with the AChR scaffold, notwithstanding activation of the MuSK‐rapsyn system of AChR clustering.