Abstract
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.
Highlights
Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ)
The aim of this study was to determine if NT1654 would benefit a mouse model of CMS caused by Agrn gene mutations
Agrnnmf380 animals were given daily injections from postnatal day 5 (P5) for 30 days with either 10 mg/kg of NT1654 (NT) or phosphate-buffered saline (PBS) (Veh), with a wild type (WT) group included for comparison
Summary
Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). Proper functioning of the neuromuscular junction (NMJ) relies on efficient signaling to the muscle This requires structural integrity of the NMJ which is mediated by a process that involves clustering of acetylcholine receptors (AChRs) at the postsynaptic membrane. MuSK recruits downstream of tyrosine kinase 7 (DOK7), which stimulates further MuSK phosphorylation (Burden et al, 2013) This causes receptor associated-protein of the synapse (RAPSYN) to form complexes with AChRs and help with their insertion into the postsynaptic membrane and anchoring to the cytoskeleton (Gervásio and Phillips, 2005). This pathway is important in both NMJ development and maintenance (Bezakova et al, 2001; Tezuka et al, 2014)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
