PMID- 24860174 OWN - NLM STAT- MEDLINE DCOM- 20150221 LR - 20211021 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 592 IP - 13 DP - 2014 Jul 1 TI - Muscle-specific kinase (MuSK) autoantibodies suppress the MuSK pathway and ACh receptor retention at the mouse neuromuscular junction. PG - 2881-97 LID - 10.1113/jphysiol.2013.270207 [doi] AB - 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 beta-subunit-Y390 was reduced at endplates. In contrast, endplate staining for beta-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. CI - (c) 2014 The Authors. The Journal of Physiology (c) 2014 The Physiological Society. FAU - Ghazanfari, Nazanin AU - Ghazanfari N AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia. FAU - Morsch, Marco AU - Morsch M AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia. FAU - Reddel, Stephen W AU - Reddel SW AD - Department of Molecular Medicine, Concord Hospital, Concord, New South Wales, 2139, Australia. FAU - Liang, Simon X AU - Liang SX AD - Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Liaoning Medical University, China. FAU - Phillips, William D AU - Phillips WD AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia william.phillips@sydney.edu.au. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140523 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Autoantibodies) RN - 0 (Immunoglobulin G) RN - 0 (Muscle Proteins) RN - 0 (Receptors, Cholinergic) RN - 0 (peripheral membrane protein 43K) RN - EC 2.7.10.1 (MuSK protein, mouse) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (src-Family Kinases) SB - IM MH - Animals MH - Autoantibodies/*pharmacology MH - Female MH - Humans MH - Immunoglobulin G/*pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Motor Endplate/drug effects/*metabolism/physiology MH - Muscle Proteins/metabolism MH - Myasthenia Gravis/immunology MH - Protein Transport MH - Receptor Protein-Tyrosine Kinases/immunology/*metabolism MH - Receptors, Cholinergic/*metabolism MH - src-Family Kinases/metabolism PMC - PMC4221826 EDAT- 2014/05/27 06:00 MHDA- 2015/02/24 06:00 PMCR- 2015/07/01 CRDT- 2014/05/27 06:00 PHST- 2014/05/27 06:00 [entrez] PHST- 2014/05/27 06:00 [pubmed] PHST- 2015/02/24 06:00 [medline] PHST- 2015/07/01 00:00 [pmc-release] AID - jphysiol.2013.270207 [pii] AID - 10.1113/jphysiol.2013.270207 [doi] PST - ppublish SO - J Physiol. 2014 Jul 1;592(13):2881-97. doi: 10.1113/jphysiol.2013.270207. Epub 2014 May 23.