Collagen Q is a key player for developing rational therapy for congenital myasthenia and for dissecting the mechanisms of anti-MuSK myasthenia gravis.
Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ) in the form of asymmetric AChE (AChE/ColQ). We exploited the proprietary NMJ-targeting signals of ColQ to treat congenital myasthenia and to explore the mechanisms of autoimmune myasthenia gravis (MG). Mutations in COLQ cause congenital endplate AChE deficiency (CEAD). First, a single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq−/− mice normalized motor functions, synaptic transmission, and partly the NMJ ultrastructure. Additionally, injection of purified recombinant AChE/ColQ protein complex into gluteus maximus accumulated AChE in non-injected forelimbs. Second, MuSK antibody-positive MG accounts for 5-15 % of MG. In vitro overlay of AChE/ColQ to muscle sections of Colq−/− mice, as well as in vitro plate-binding of MuSK to ColQ, revealed thatMuSK-IgG blocks binding of ColQ to MuSK in a dose-dependent manner. Passive transfer of MuSK-IgG to wild-type mice markedly reduced the size and intensity of ColQ signals at NMJs. MuSK-IgG thus interferes with binding of ColQ to MuSK. Elucidation of molecular mechanisms of specific binding of ColQ to NMJ enabled us to ameliorate devastating myasthenic symptoms of Colq−/− mice and also to reveal underlying mechanisms of anti-MuSK-MG.
Kinji
K
Ohno
Mikako
M
Ito
Yu
Y
Kawakami
Kenji
K
Ohtsuka
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009045:Motor Endplate / Q000187:drug effects / Q000378:metabolism; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000378:metabolism*; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D011950:Receptors, Cholinergic; D003094:Collagen; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000110:Acetylcholinesterase