Lookup NU author(s): Dr Grace McMacken,
Dr Andreas Roos,
Dr Roger Whittaker,
Professor Hanns Lochmuller
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective ß2 adrenergic agonist salbutamol and the a and ß adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective ß2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via ß2 adrenoceptors and via a cAMP-dependent pathway.
Author(s): McMacken G, Cox D, Roos A, Müller J, Whittaker R, Lochmüller H
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Print publication date: 01/05/2018
Online publication date: 16/02/2018
Acceptance date: 14/02/2018
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
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