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FASEB J. 2016 Jun;30(6):2382-99. doi: 10.1096/fj.201500162. Epub 2016 Mar 18.

Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency.

Author information

1
Centre de Neurophysique, Physiologie et Pathologie, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8119, Université Paris Descartes, Sorbonne Paris Cité, Paris France;
2
Commissariat à l'énergie Atomique et aux Energies Alternatives, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif sur Yvette, France; Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS/Université Paris-Sud, Paris, France; and.
3
Institut de Recherche Thérapeutique de l'Université de Nantes, Plateforme Génomique Intégrative, Nantes, France.
4
Centre de Neurophysique, Physiologie et Pathologie, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8119, Université Paris Descartes, Sorbonne Paris Cité, Paris France; claire.legay@parisdescartes.fr.

Abstract

The collagen ColQ anchors acetylcholinesterase (AChE) in the synaptic cleft of the neuromuscular junction (NMJ). It also binds MuSK and perlecan/dystroglycan, 2 signaling platforms of the postsynaptic domain. Mutations in ColQ cause a congenital myasthenic syndrome (CMS) with AChE deficiency. Because the absence of AChE does not fully explain the complexity of the syndrome and there is no curative treatment for the disease, we explored additional potential targets of ColQ by conducting a large genetic screening of ColQ-deficient mice, a model for CMS with AChE deficiency, and analyzed their NMJ and muscle phenotypes. We demonstrated that ColQ controls the development and the maturation of the postsynaptic domain by regulating synaptic gene expression. Notably, ColQ deficiency leads to an up-regulation of the 5 subunits of the nicotinic acetylcholine receptor (AChR), leading to mixed mature and immature AChRs at the NMJ of adult mice. ColQ also regulates the expression of extracellular matrix (ECM) components. However, whereas the ECM mRNAs were down-regulated in vitro, compensation seemed to occur in vivo to maintain normal levels of these mRNAs. Finally, ColQ deficiency leads to a general atrophic phenotype and hypoplasia that affect fast muscles. This study points to new specific hallmarks for this CMS.-Sigoillot, S. M., Bourgeois, F., Karmouch, J., Molgó, J., Dobbertin, A., Chevalier, C., Houlgatte, R., Léger, J., Legay, C. Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency.

KEYWORDS:

AChR; collagen Q; dystroglycan; extracellular matrix; gene profiling

PMID:
26993635
DOI:
10.1096/fj.201500162
[Indexed for MEDLINE]

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