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Collagen Q is a Key Player for Developing Rational Therapy for Congenital Myasthenia and for Dissecting the Mechanisms of Anti-MuSK Myasthenia Gravis
- Source :
- Journal of Molecular Neuroscience. 53:359-361
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
Abstract
- 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 that MuSK-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.
- Subjects :
- medicine.medical_specialty
Aché
Neurotransmission
Motor Endplate
Antibodies
Neuromuscular junction
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Internal medicine
COLQ
medicine
Animals
Humans
Receptors, Cholinergic
Myasthenic Syndromes, Congenital
Chemistry
Receptor Protein-Tyrosine Kinases
General Medicine
Congenital myasthenic syndrome
medicine.disease
Acetylcholinesterase
Myasthenia gravis
language.human_language
Myasthenia Gravis, Autoimmune, Experimental
Cell biology
medicine.anatomical_structure
Endocrinology
language
Basal lamina
Collagen
Subjects
Details
- ISSN :
- 15591166 and 08958696
- Volume :
- 53
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular Neuroscience
- Accession number :
- edsair.doi.dedup.....116e0527596d73a4b7590abbc533cdc1