PMID- 22789393
OWN - NLM
STAT- MEDLINE
DCOM- 20121113
LR  - 20120914
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 237
IP  - 2
DP  - 2012 Oct
TI  - Muscle specific kinase autoantibodies cause synaptic failure through progressive 
      wastage of postsynaptic acetylcholine receptors.
PG  - 286-95
LID - S0014-4886(12)00276-2 [pii]
LID - 10.1016/j.expneurol.2012.06.034 [doi]
AB  - In myasthenia gravis muscle weakness is caused by autoantibodies against 
      components of the neuromuscular junction. Patient autoantibodies against muscle 
      specific kinase (MuSK) deplete MuSK from the postsynaptic membrane and reproduce 
      signs of myasthenia gravis when injected into mice. Here we have examined the 
      time-course of structural and functional changes that lead up to synaptic 
      failure. C57Bl6J mice received daily injections of anti-MuSK patient IgG for 15 
      days. Mice began to lose weight from day 12 and demonstrated whole-body weakness 
      by day 14. Electromyography indicated synaptic impairment from day 6 in the 
      gastrocnemius muscle and from day 10 in the diaphragm muscle. Confocal microscopy 
      revealed linear declines in the area and density of postsynaptic acetylcholine 
      receptors (3-5% per day) from day 1 through day 15 of the injection series in all 
      five muscles examined. Intracellular recordings from the diaphragm muscle 
      revealed comparable progressive declines in the amplitude of the endplate 
      potential and miniature endplate potential of 3-4% per day. Neither quantal 
      content nor the postsynaptic action potential threshold changed significantly 
      over the injection series. The inverse relationship between the quantal amplitude 
      of a synapse and its quantal content disappeared only late in the injection 
      series (day 10). Our results suggest that the primary myasthenogenic action of 
      anti-MuSK IgG is to cause wastage of postsynaptic acetylcholine receptor density. 
      Consequent reductions in endplate potential amplitudes culminated in failure of 
      neuromuscular transmission.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Morsch, Marco
AU  - Morsch M
AD  - School of Medical Sciences-Physiology and Bosch Institute, University of Sydney, 
      Sydney, New South Wales 2006, Australia.
FAU - Reddel, Stephen W
AU  - Reddel SW
FAU - Ghazanfari, Nazanin
AU  - Ghazanfari N
FAU - Toyka, Klaus V
AU  - Toyka KV
FAU - Phillips, William D
AU  - Phillips WD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120710
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Autoantibodies)
RN  - 0 (Autoantigens)
RN  - 0 (Receptors, Cholinergic)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Action Potentials/physiology
MH  - Animals
MH  - Autoantibodies/*immunology
MH  - Autoantigens/immunology
MH  - Electromyography
MH  - Female
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Confocal
MH  - Myasthenia Gravis/immunology/*metabolism/physiopathology
MH  - Neuromuscular Junction/immunology/*metabolism/physiopathology
MH  - Receptor Protein-Tyrosine Kinases/*immunology
MH  - Receptors, Cholinergic/*metabolism
MH  - Synapses
MH  - Synaptic Transmission/physiology
EDAT- 2012/07/14 06:00
MHDA- 2012/11/14 06:00
CRDT- 2012/07/14 06:00
PHST- 2012/05/18 00:00 [received]
PHST- 2012/06/27 00:00 [revised]
PHST- 2012/06/28 00:00 [accepted]
PHST- 2012/07/14 06:00 [entrez]
PHST- 2012/07/14 06:00 [pubmed]
PHST- 2012/11/14 06:00 [medline]
AID - S0014-4886(12)00276-2 [pii]
AID - 10.1016/j.expneurol.2012.06.034 [doi]
PST - ppublish
SO  - Exp Neurol. 2012 Oct;237(2):286-95. doi: 10.1016/j.expneurol.2012.06.034. Epub 
      2012 Jul 10.