title: Myasthenia gravis experimentally induced with muscle-specific kinase.
abstract: 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.
authors: Department of Preventive Medicine, Ehime University School of Medicine, Ehime, Japan. kazshige@tmig.or.jp
authors: Kazuhiro
authors: K
authors: Shigemoto
authors: Sachiho
authors: S
authors: Kubo
authors: Chen
authors: C
authors: Jie
authors: Naohito
authors: N
authors: Hato
authors: Yasuhito
authors: Y
authors: Abe
authors: Norifumi
authors: N
authors: Ueda
authors: Naoto
authors: N
authors: Kobayashi
authors: Kenji
authors: K
authors: Kameda
authors: Katsumi
authors: K
authors: Mominoki
authors: Atsuo
authors: A
authors: Miyazawa
authors: Akihito
authors: A
authors: Ishigami
authors: Seiji
authors: S
authors: Matsuda
authors: Naoki
authors: N
authors: Maruyama
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D005810:Multigene Family / Q000235:genetics; D009157:Myasthenia Gravis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D011950:Receptors, Cholinergic; D020794:Receptor Protein-Tyrosine Kinases