C. elegans: Model organism of human congenital myasthenic syndromes

RAYES DIEGO; HERNANDO GUILLERMINA; JONES AK; AL DIWANI A; MAYNARD TPR; JONES R; MATTHEWS S; BUCKINGHAM S; SATTELLE DAVID; BOUZAT CECILIA

Bahía Blanca

Workshop; Workshop Neuronal Comunication: from structure to physiology. Sociedad Argentina de Investigación en Neurociencias; 2008

Sociedad Argentina de Investigación en Neurociencias

The nematode Caenorhabditis elegans is an established model organism for studying neurobiology and is emerging as a useful vehicle for investigating nervous system and neuromuscular disorders. UNC-63 is a C. elegans nicotinic acetylcholine receptor (nAChR) alpha subunit that plays an important role in cholinergic synaptic transmission at the nematode neuromuscular junction (NMJ). Here we show that worms with the unc-63(x26) allelle, with its alphaC151Y mutation that disrupts the Cys-loop, have deficient muscle function as displayed by impaired thrashing locomotion compared to wild-type worms. Single-channel recordings from muscle cells of the mutant strain show fewer active patches, a 100-fold reduced frequency of opening events, and abnormally reduced duration of channel openings compared to wild type muscle. These observations can be explained by a decrease in nAChR expression at the cell surface together with impaired opening and fast channel closing, similar to the observations in some patients with congenital myasthenia syndromes (CMS) caused by loss of function mutations at the neuromuscular nAChRs. Interestingly, a mutation in the equivalent position of the e subunit of the human muscle nAChR (epsylonC128S) is associated with a CMS due to nAChR deficiency at the endplate. Therefore, disruption of the Cys-loop results in qualitatively similar actions on both nematode and human receptors. Therapy for CMS caused by loss of function mutations in nAChRs is limited in variety and success with 3,4-diaminopyridine (3,4-DAP) and anticholinesterase drugs such as pyridostigmine bromide (PB). We show that PB and 3,4-DAP can partially rescue the motility defect seen in unc-63(x26), making this the first C. elegans model for screening drug candidates aimed at ameliorating the consequences of CMS associated with decreased response to ACh during neuromuscular transmission