title: Muscle-specific kinase (MuSK) autoantibodies suppress the MuSK pathway and ACh receptor retention at the mouse neuromuscular junction.
abstract: Muscle-specific kinase (MuSK) autoantibodies from myasthenia gravis patients can block the activation of MuSK in vitro and/or reduce the postsynaptic localization of MuSK. Here we use a mouse model to examine the effects of MuSK autoantibodies upon some key components of the postsynaptic MuSK pathway and upon the regulation of junctional ACh receptor (AChR) numbers. Mice became weak after 14 daily injections of anti-MuSK-positive patient IgG. The intensity and area of AChR staining at the motor endplate was markedly reduced. Pulse-labelling of AChRs revealed an accelerated loss of pre-existing AChRs from postsynaptic AChR clusters without a compensatory increase in incorporation of (newly synthesized) replacement AChRs. Large, postsynaptic AChR clusters were replaced by a constellation of tiny AChR microaggregates. Puncta of AChR staining also appeared in the cytoplasm beneath the endplate. Endplate staining for MuSK, activated Src, rapsyn and AChR were all reduced in intensity. In the tibialis anterior muscle there was also evidence that phosphorylation of the AChR β-subunit-Y390 was reduced at endplates. In contrast, endplate staining for β-dystroglycan (through which rapsyn couples AChR to the synaptic basement membrane) remained intense. The results suggest that anti-MuSK IgG suppresses the endplate density of MuSK, thereby down-regulating MuSK signalling activity and the retention of junctional AChRs locally within the postsynaptic membrane scaffold.
authors.affiliation: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Ghazanfari
authors.affiliation: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Marco
authors.initials: M
authors.lastname: Morsch
authors.affiliation: Department of Molecular Medicine, Concord Hospital, Concord, New South Wales, 2139, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Reddel
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Liaoning Medical University, China.
authors.forename: Simon X
authors.initials: SX
authors.lastname: Liang
authors.affiliation: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia william.phillips@sydney.edu.au.
authors.forename: William D
authors.initials: WD
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009045:Motor Endplate / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D009157:Myasthenia Gravis / Q000276:immunology; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases