title: Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes.
abstract: OBJECTIVE
  To determine the pathogenesis of anti-muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and
  
  
  METHODS
  Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy.
  
  
  RESULTS
  Animals immunized with 100 μg of MuSK 60 developed severe progressive weakness starting at day 16, with 100% mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity.
  
  
  CONCLUSIONS
  These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.
authors.affiliation: Department of Neurology, University of California-Davis, 1515 Newton Ct., Davis, CA 95616, USA. dprichman@ucdavis.edu
authors.forename: David P
authors.initials: DP
authors.lastname: Richman
authors.forename: Kayoko
authors.initials: K
authors.lastname: Nishi
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Morell
authors.forename: Jolene Mi
authors.initials: JM
authors.lastname: Chang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ferns
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wollmann
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Maselli
authors.forename: Joachim
authors.initials: J
authors.lastname: Schnier
authors.forename: Mark A
authors.initials: MA
authors.lastname: Agius
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D002038:Bungarotoxins / Q000493:pharmacokinetics; D002802:Cholinesterases / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006614:Hindlimb / Q000503:physiopathology; D008475:Median Nerve / Q000502:physiology; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009157:Myasthenia Gravis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000473:pathology* / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D020794:Receptor Protein-Tyrosine Kinases / Q000009:adverse effects* / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D002038:Bungarotoxins; D011950:Receptors, Cholinergic; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D002802:Cholinesterases