Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 21, Issue 10, Pages 949-958Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14728222.2017.1369960
Keywords
Acetylcholine receptor; agrin; LRP4; MuSK; congenital myasthenic syndromes; myasthenia gravis
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [15H04840]
- Ministry of Health, Labour and Welfare of Japan [H29-Nanchi-Ippan-030]
- Japan Agency for Medical Research and Development [17gm1010002h0002, 17ek0109230h0001, 17ek0109281h0001]
- Smoking Research Foundation
- Intramural Research Grant for NCNP [29-4]
- Grants-in-Aid for Scientific Research [15K06707, 15H04840] Funding Source: KAKEN
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Introduction: Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, a-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few. Areas covered: This review covers the agrin-LRP4-MuSK signaling pathway, which drives clustering of acetylcholine receptors (AChRs) and ensures efficient signal transduction at the NMJ. We also address diseases caused by autoantibodies against the NMJ molecules and by germline mutations in genes encoding the NMJ molecules. Expert opinion: Representative small compounds to treat the defective NMJ signal transduction are cholinesterase inhibitors, which exert their effects by increasing the amount of acetylcholine at the synaptic space. Another possible therapeutic strategy to enhance the NMJ signal transduction is to increase the number of AChRs, but no currently available drug has this functionality.
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