Induction of myasthenia by immunization against muscle-specific kinase.

Abstract	Muscle-specific kinase (MuSK) is critical for the synaptic clustering of nicotinic acetylcholine receptors (AChRs) and plays multiple roles in the organization and maintenance of neuromuscular junctions (NMJs). MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering at the postsynaptic membrane. Although autoantibodies against the ectodomain of MuSK have been found in a proportion of patients with generalized myasthenia gravis (MG), it is unclear whether MuSK autoantibodies are the causative agent of generalized MG. In the present study, rabbits immunized with MuSK ectodomain protein manifested MG-like muscle weakness with a reduction of AChR clustering at the NMJs. The autoantibodies activated MuSK and blocked AChR clustering induced by agrin or by mediators that do not activate MuSK. Thus MuSK autoantibodies rigorously inhibit AChR clustering mediated by multiple pathways, an outcome that broadens our general comprehension of the pathogenesis of MG.
Authors	Kazuhiro Shigemoto, Sachiho Kubo, Naoki Maruyama, Naohito Hato, Hiroyuki Yamada, Chen Jie, Naoto Kobayashi, Katsumi Mominoki, Yasuhito Abe, Norifumi Ueda, Seiji Matsuda
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 116 Issue 4 Pg. 1016-24 (Apr 2006) ISSN: 0021-9738 [Print] United States
PMID	16557298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Agrin Autoantibodies Receptors, Cholinergic Receptors, Nicotinic Recombinant Proteins MUSK protein, human Receptor Protein-Tyrosine Kinases Neuraminidase
Topics	Agrin (metabolism, pharmacology) Animals Autoantibodies (biosynthesis) Cells, Cultured Enzyme Activation (immunology) Humans Immunization Mice Models, Biological Muscle Hypotonia (metabolism) Muscles (metabolism) Myasthenia Gravis (etiology, immunology, metabolism) Neuraminidase (metabolism) Neuromuscular Junction (immunology) Protein Structure, Tertiary Rabbits Receptor Protein-Tyrosine Kinases (immunology, metabolism) Receptors, Cholinergic (immunology, metabolism) Receptors, Nicotinic (immunology, metabolism) Recombinant Proteins (genetics, metabolism) Signal Transduction Species Specificity

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