Transgenic C. elegans as a model of congenital myasthenic syndromes

BERGE, I.; HERNANDO, G.; BOUZAT, C.

Huerta Grande, Córdoba

Congreso; XXVII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2012

The  free  living  nematode  Caenorhabditis  elegans  is  a  model for  the  study  of human  neurological  diseases  and  drug testing.  Our  goal  is  to  establish  C. elegans  as  a  model of  slow-channel  congenital  myasthenic  syndromes,  which are originated  by  gain-of-function  mutations  in  nicotinic receptor  subunits.  We introduced a mutation in the 9? position of the M2 domain of UNC-38 (V9?S), an essential  alpha-type  subunit of  muscle  levamisole-sensitive  nicotinic  receptor (L-AChR), and generated transgenic worms that express the mutant subunit in muscle. Single-channel recordings from isolated muscle cells show a dramatic increase  (about  10-fold)  in  the  open  duration  of L-AChR  channels.  Single openings appear, in contrast to wild-type channels, grouped into long activation periods. Macroscopic currents are 3-fold smaller than wild-type currents and do not  decay  in the  presence  of  ACh.  The  functional  changes  of  L-AChR  in the mutant worm mimic those observ    ed in vertebrate AChRs carrying the equivalent mutation. Our results reveal a high degree of conservation of functional roles of amino  acids  between  C. elegans  and  human  AChRs,  thus  opening  doors  for studying other  gain-of-function  mutations  associated  to  slow-channel syndromes.