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: Shuuichi Mori, Sachiho Kubo, Takuyu Akiyoshi, Shigeru Yamada, Tsuyoshi Miyazaki, Harumi Hotta, Junzo Desaki, Masahiko Kishi, Tetsuro Konishi, Yuri Nishino, Atsuo Miyazawa, Naoki Maruyama, Kazuhiro Shigemoto
• Journal: The American journal of pathology (Am J Pathol) Vol. 180 Issue 2 Pg. 798-810 (Feb 2012) ISSN: 1525-2191 [Electronic] United States
• PMID: 22142810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Autoantibodies
• Cholinesterase Inhibitors
• Complement C5
• Immunoglobulin G
• Recombinant Proteins
• MuSK protein, mouse
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Autoantibodies (physiology)
• Cholinesterase Inhibitors (pharmacology)
• Complement C5 (deficiency)
• Immunoglobulin G (physiology)
• Mice
• Mice, Inbred Strains
• Muscle Strength (physiology)
• Muscle Weakness (immunology)
• Myasthenia Gravis, Autoimmune, Experimental (immunology, pathology)
• Neuromuscular Junction (immunology, pathology, ultrastructure)
• Receptor Protein-Tyrosine Kinases (immunology)
• Recombinant Proteins
• Signal Transduction
• Synapses (immunology, pathology, physiology)
• Synaptic Transmission (physiology)
• Weight Loss (physiology)