PMID- 26702075
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151224
LR  - 20210109
IS  - 2051-817X (Print)
IS  - 2051-817X (Electronic)
IS  - 2051-817X (Linking)
VI  - 3
IP  - 12
DP  - 2015 Dec
TI  - Forced expression of muscle specific kinase slows postsynaptic acetylcholine 
      receptor loss in a mouse model of MuSK myasthenia gravis.
LID - 10.14814/phy2.12658 [doi]
LID - e12658
AB  - We investigated the influence of postsynaptic tyrosine kinase signaling in a 
      mouse model of muscle-specific kinase (MuSK) myasthenia gravis (MG). Mice 
      administered repeated daily injections of IgG from MuSK MG patients developed 
      impaired neuromuscular transmission due to progressive loss of acetylcholine 
      receptor (AChR) from the postsynaptic membrane of the neuromuscular junction. In 
      this model, anti-MuSK-positive IgG caused a reduction in motor endplate 
      immunolabeling for phosphorylated Src-Y418 and AChR beta-subunit-Y390 before any 
      detectable loss of MuSK or AChR from the endplate. Adeno-associated viral vector 
      (rAAV) encoding MuSK fused to enhanced green fluorescent protein (MuSK-EGFP) was 
      injected into the tibialis anterior muscle to increase MuSK synthesis. When mice 
      were subsequently challenged with 11 daily injections of IgG from MuSK MG 
      patients, endplates expressing MuSK-EGFP retained more MuSK and AChR than 
      endplates of contralateral muscles administered empty vector. Recordings of 
      compound muscle action potentials from myasthenic mice revealed less impairment 
      of neuromuscular transmission in muscles that had been injected with 
      rAAV-MuSK-EGFP than contralateral muscles (empty rAAV controls). In contrast to 
      the effects of MuSK-EGFP, forced expression of rapsyn-EGFP provided no such 
      protection to endplate AChR when mice were subsequently challenged with MuSK MG 
      IgG. In summary, the immediate in vivo effect of MuSK autoantibodies was to 
      suppress MuSK-dependent tyrosine phosphorylation of proteins in the postsynaptic 
      membrane, while increased MuSK synthesis protected endplates against AChR loss. 
      These results support the hypothesis that reduced MuSK kinase signaling initiates 
      the progressive disassembly of the postsynaptic membrane scaffold in this mouse 
      model of MuSK MG.
CI  - (c) 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on 
      behalf of the American Physiological Society and The Physiological Society.
FAU - Ghazanfari, Nazanin
AU  - Ghazanfari N
AD  - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 
      Australia.
FAU - Linsao, Erna L T B
AU  - Linsao EL
AD  - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 
      Australia.
FAU - Trajanovska, Sofie
AU  - Trajanovska S
AD  - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 
      Australia.
FAU - Morsch, Marco
AU  - Morsch M
AD  - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 
      Australia Department of Biomedical Sciences, Macquarie University, Sydney, New 
      South Wales, Australia.
FAU - Gregorevic, Paul
AU  - Gregorevic P
AD  - Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
FAU - Liang, Simon X
AU  - Liang SX
AD  - Department of Biochemistry and Molecular Biology, College of Basic Medical 
      Sciences, Liaoning Medical University, Liaoning, China.
FAU - Reddel, Stephen W
AU  - Reddel SW
AD  - Department of Molecular Medicine, Concord Hospital, Sydney, New South Wales, 
      Australia.
FAU - Phillips, William D
AU  - Phillips WD
AD  - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 
      Australia william.phillips@sydney.edu.au.
LA  - eng
PT  - Journal Article
DEP - 20151222
PL  - United States
TA  - Physiol Rep
JT  - Physiological reports
JID - 101607800
PMC - PMC4760443
OTO - NOTNLM
OT  - myasthenia
OT  - neuromuscular junction
OT  - synapse formation
OT  - tyrosine kinase
EDAT- 2015/12/25 06:00
MHDA- 2015/12/25 06:01
PMCR- 2015/12/23
CRDT- 2015/12/25 06:00
PHST- 2015/11/15 00:00 [received]
PHST- 2015/11/20 00:00 [accepted]
PHST- 2015/12/25 06:00 [entrez]
PHST- 2015/12/25 06:00 [pubmed]
PHST- 2015/12/25 06:01 [medline]
PHST- 2015/12/23 00:00 [pmc-release]
AID - 3/12/e12658 [pii]
AID - PHY212658 [pii]
AID - 10.14814/phy2.12658 [doi]
PST - ppublish
SO  - Physiol Rep. 2015 Dec;3(12):e12658. doi: 10.14814/phy2.12658. Epub 2015 Dec 22.