PMID- 20603331
OWN - NLM
STAT- MEDLINE
DCOM- 20110620
LR  - 20240503
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 588
IP  - Pt 17
DP  - 2010 Sep 1
TI  - Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to 
      disassembly of the ACh receptor scaffold and myasthenia gravis in mice.
PG  - 3217-29
LID - 10.1113/jphysiol.2010.190298 [doi]
AB  - 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 
      beta-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.
FAU - Cole, R N
AU  - Cole RN
AD  - Physiology, Anderson Stuart Bldg (F13), University of Sydney, NSW 2006 Australia.
FAU - Ghazanfari, N
AU  - Ghazanfari N
FAU - Ngo, S T
AU  - Ngo ST
FAU - Gervasio, O L
AU  - Gervasio OL
FAU - Reddel, S W
AU  - Reddel SW
FAU - Phillips, W D
AU  - Phillips WD
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100705
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Autoantibodies)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, Cholinergic)
RN  - EC 2.7.10.1 (MUSK protein, human)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Animals
MH  - Autoantibodies/*physiology/toxicity
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Immunoglobulin G/physiology/toxicity
MH  - Matrix Attachment Regions/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myasthenia Gravis/enzymology/etiology/*metabolism
MH  - Neuromuscular Junction/enzymology/genetics/*metabolism
MH  - Receptor Protein-Tyrosine Kinases/*antagonists & 
      inhibitors/*deficiency/immunology/metabolism
MH  - Receptors, Cholinergic/chemistry/deficiency/immunology/*metabolism
MH  - Synapses/*enzymology/genetics/metabolism
PMC - PMC2976017
EDAT- 2010/07/07 06:00
MHDA- 2011/06/21 06:00
PMCR- 2011/09/01
CRDT- 2010/07/07 06:00
PHST- 2010/07/07 06:00 [entrez]
PHST- 2010/07/07 06:00 [pubmed]
PHST- 2011/06/21 06:00 [medline]
PHST- 2011/09/01 00:00 [pmc-release]
AID - jphysiol.2010.190298 [pii]
AID - 10.1113/jphysiol.2010.190298 [doi]
PST - ppublish
SO  - J Physiol. 2010 Sep 1;588(Pt 17):3217-29. doi: 10.1113/jphysiol.2010.190298. Epub 
      2010 Jul 5.