title: [Molecular bases and therapeutic strategies in defective neuromuscular transmissions: lessons learned from a prototypical synapse].
abstract: Neuromuscular junction is a prototypical synapse, and most synaptic molecules expressed in the central nervous system have been first identified at the neuromuscular junction. Congenital myasthenic syndromes are caused by genetic defects of molecules expressed at the neuromuscular junction. We have identified and characterized five defective molecules. (1) Defects in choline acetyltransferase reduce acetylcholine contents at the nerve terminal. (2) Collagen Q (ColQ) anchors acetylcholinesterase at the synaptic basal lamina, and its defects cause endplate acetylcholinesterase deficiency. ColQ has an anchoring signal to the synaptic basal lamina. ColQ expressed in a limited number of muscle cells efficiently ameliorates myasthenic symptoms in mice. (3) Loss-of-function mutations of acetylcholine receptor (AChR) cause either endplate AChR deficiency or fast channel syndrome. Gain-of-function mutations cause slow channel syndrome, in which calcium overloading provokes endplate myopathy. (4) Rapsyn clusters AChR at the endplate, and its defects cause endplate AChR deficiency. (5) Loss-of-function mutations of skeletal muscle voltage-gated sodium channel cause myasthenia by abrogating the propagation of muscle action potentials. We need to further pursue the molecular bases and the therapeutic strategies of defective neuromuscular transmissions, and hopefully expand our analysis to defective synapse transmissions in the central nervous system.
authors.affiliation: Division of Neurogenetics, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. ohnok@med.nagoya-u.ac.jp
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.forename: Mikako
authors.initials: M
authors.lastname: Ito
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics; D000818:Animals; D002490:Central Nervous System; D002795:Choline O-Acetyltransferase / Q000235:genetics; D003094:Collagen / Q000235:genetics; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics / Q000628:therapy; D009469:Neuromuscular Junction / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics; D013569:Synapses
chemical_list: D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D015222:Sodium Channels; C051609:peripheral membrane protein 43K; D003094:Collagen; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; C114027:COLQ protein, human