title: Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis.
abstract: Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MuSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans.
authors.affiliation: Department of Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Shuuichi
authors.initials: S
authors.lastname: Mori
authors.forename: Sachiho
authors.initials: S
authors.lastname: Kubo
authors.forename: Takuyu
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Harumi
authors.initials: H
authors.lastname: Hotta
authors.forename: Junzo
authors.initials: J
authors.lastname: Desaki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kishi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Konishi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nishino
authors.forename: Atsuo
authors.initials: A
authors.lastname: Miyazawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Maruyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shigemoto
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003182:Complement C5 / Q000172:deficiency; D007074:Immunoglobulin G / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D053580:Muscle Strength / Q000502:physiology; D018908:Muscle Weakness / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D009469:Neuromuscular Junction / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D013569:Synapses / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D015431:Weight Loss / Q000502:physiology
chemical_list: D001323:Autoantibodies; D002800:Cholinesterase Inhibitors; D003182:Complement C5; D007074:Immunoglobulin G; D011994:Recombinant Proteins; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases