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Modulation of the Acetylcholine Receptor Clustering Pathway Improves Neuromuscular Junction Structure and Muscle Strength in a Mouse Model of Congenital Myasthenic Syndrome

Lookup NU author(s): Dr Sally Spendiff, Rachel Howarth, Dr Grace McMacken, Tracey DaveyORCiD, Dr Andreas Roos, Professor Rita HorvathORCiD, Professor Hanns Lochmuller



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© Copyright © 2020 Spendiff, Howarth, McMacken, Davey, Quinlan, O'Connor, Slater, Hettwer, Mäder, Roos, Horvath and Lochmüller.Introduction: Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). CMS often present early with fatigable weakness and can be fatal through respiratory complications. The AGRN gene is one of over 30 genes known to harbor mutations causative for CMS. In this study, we aimed to determine if a compound (NT1654), developed to stimulate the acetylcholine receptor (AChR) clustering pathway, would benefit a mouse model of CMS caused by a loss-of-function mutation in Agrn (Agrnnmf380 mouse). Methods: Agrnnmf380 mice received an injection of either NT1654 or vehicle compound daily, with wild-type litter mates used for comparison. Animals were weighed daily and underwent grip strength assessments. After 30 days of treatment animals were sacrificed, and muscles collected. Investigations into NMJ and muscle morphology were performed on collected tissue. Results: While minimal improvements in NMJ ultrastructure were observed with electron microscopy, gross NMJ structure analysis using fluorescent labelling and confocal microscopy revealed extensive postsynaptic improvements in Agrnnmf380 mice with NT1654 administration, with variables frequently returning to wild type levels. An improvement in muscle weight and myofiber characteristics helped increase forelimb grip strength and body weight. Conclusions: We conclude that NT1654 restores NMJ postsynaptic structure and improves muscle strength through normalization of muscle fiber composition and the prevention of atrophy. We hypothesize this occurs through the AChR clustering pathway in Agrnnmf380 mice. Future studies should investigate if this may represent a viable treatment option for patients with CMS, especially those with mutations in proteins of the AChR clustering pathway.

Publication metadata

Author(s): Spendiff S, Howarth R, McMacken G, Davey T, Quinlan K, O'Connor E, Slater C, Hettwer S, Mader A, Roos A, Horvath R, Lochmuller H

Publication type: Article

Publication status: Published

Journal: Frontiers in Molecular Neuroscience

Year: 2020

Volume: 13

Online publication date: 17/12/2020

Acceptance date: 24/11/2020

Date deposited: 09/03/2021

ISSN (electronic): 1662-5099

Publisher: Frontiers Media S.A.


DOI: 10.3389/fnmol.2020.594220


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