PMID- 18096854
OWN - NLM
STAT- MEDLINE
DCOM- 20080908
LR  - 20091119
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 1132
DP  - 2008
TI  - Myasthenia gravis experimentally induced with muscle-specific kinase.
PG  - 93-8
AB  - Here we present the first evidence that muscle-specific kinase (MuSK) antigen can 
      cause myasthenia in animals. MuSK is expressed at the postsynaptic membranes of 
      neuromuscular junctions (NMJ) and forms complexes with acetylcholine receptors 
      (AChR) and rapsyn. MuSK is activated by agrin, which is released from 
      motoneurons, and induces AChR clustering and subsequent formation of NMJ in 
      embryos. Notably, autoantibodies against MuSK were found in a proportion of 
      patients with generalized myasthenia gravis (MG) but without the characteristic 
      AChR autoantibodies. However, MuSK autoantibodies had no known pathogenic 
      potential, and animals immunized with purified MuSK proteins did not develop MG 
      in former studies. In contrast, we have now injected rabbits with MuSK ectodomain 
      protein in vivo and evoked a MG-like muscle weakness with a reduction of AChR 
      clustering at the NMJ. Our results showed that MuSK is required for maintenance 
      of synapses and that interference with that function by MuSK antibodies causes 
      myasthenic weakness. In vitro, AChR clustering in myotubes is induced by agrin 
      and agrin-independent inducers, which do not activate MuSK. Neither the receptor 
      nor the activation mechanisms of AChR clustering induced by agrin-independent 
      inducers has been identified with certainty, but MuSK autoantibodies in 
      myasthenic animals inhibited both agrin and agrin-independent AChR clustering. 
      MuSK plays multiple roles in pre-patterning of the postsynaptic membrane before 
      innervation and formation of NMJ in embryos. Some of these mechanisms may also 
      participate in the maintenance of mature NMJ. This model system would provide new 
      knowledge about the molecular pathogenesis of MG and MuSK functions in mature 
      NMJ.
FAU - Shigemoto, Kazuhiro
AU  - Shigemoto K
AD  - Department of Preventive Medicine, Ehime University School of Medicine, Ehime, 
      Japan. kazshige@tmig.or.jp
FAU - Kubo, Sachiho
AU  - Kubo S
FAU - Jie, Chen
AU  - Jie C
FAU - Hato, Naohito
AU  - Hato N
FAU - Abe, Yasuhito
AU  - Abe Y
FAU - Ueda, Norifumi
AU  - Ueda N
FAU - Kobayashi, Naoto
AU  - Kobayashi N
FAU - Kameda, Kenji
AU  - Kameda K
FAU - Mominoki, Katsumi
AU  - Mominoki K
FAU - Miyazawa, Atsuo
AU  - Miyazawa A
FAU - Ishigami, Akihito
AU  - Ishigami A
FAU - Matsuda, Seiji
AU  - Matsuda S
FAU - Maruyama, Naoki
AU  - Maruyama N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071220
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (Autoantibodies)
RN  - 0 (Receptors, Cholinergic)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Animals
MH  - Autoantibodies/immunology
MH  - Disease Models, Animal
MH  - Humans
MH  - Multigene Family/genetics
MH  - Myasthenia Gravis/*enzymology/genetics/immunology/pathology
MH  - Receptor Protein-Tyrosine Kinases/genetics/immunology/*metabolism
MH  - Receptors, Cholinergic/genetics/immunology/*metabolism
EDAT- 2007/12/22 09:00
MHDA- 2008/09/09 09:00
CRDT- 2007/12/22 09:00
PHST- 2007/12/22 09:00 [pubmed]
PHST- 2008/09/09 09:00 [medline]
PHST- 2007/12/22 09:00 [entrez]
AID - annals.1405.002 [pii]
AID - 10.1196/annals.1405.002 [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2008;1132:93-8. doi: 10.1196/annals.1405.002. Epub 2007 Dec 20.