Establishing C. elegans models of human congenital myasthenic syndromes

Autores
Bergé, Ignacio; Hernando, Guillermina Silvana; Bouzat, Cecilia Beatriz
Año de publicación
2013
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
The free-living nematode Caenorhabditis elegans is a model for the study of human neurological diseases and drug testing. In humans, gain-of-function mutations in muscle nicotinic receptor (AChR) subunits lead to slow-channel congenital myasthenic syndromes. We here explored if homologous mutations in C. elegans subunits mimic the molecular and functional changes observed in patients. In the essential UNC-38 and UNC-29 subunits of the levamisole-sensitive AChR (L-AChR) we mutated residues at position 9’ of M2, which forms the gate of the channel, and position 12’, which mimics a mutation found in a patient. We generated transgenic worms expressing the mutant AChRs in muscle using both wild-type and null-mutant strains as backgrounds. Electrophysiological studies show a dramatic increase (14-fold) in the open duration of L-AChR channels, and a decrease in the desensitization rate of macroscopic currents elicited by ACh, similarly to the changes detected in human mutant AChRs. Unexpectedly, no significant changes in locomotion and levamisole-sensitivity of transgenic worms occur. Overall, our results show that mutant subunits are incorporated into functional L-AChRs and lead to kinetic changes similar to those observed in vertebrate AChRs, thus revealing a high degree of conservation of functional roles of amino acids between C. elegans and human AChRs. These results open doors for establishing C. elegans models for human myasthenic syndromes.
Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Hernando, Guillermina Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
XXVIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias
Huerta Grande
Argentina
Sociedad Argentina de Investigación en Neurociencias
Materia
C ELEGANS
MYASTHENIC SYNDROMES
PATCH-CLAMP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/235311
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/235311
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Establishing C. elegans models of human congenital myasthenic syndromesBergé, IgnacioHernando, Guillermina SilvanaBouzat, Cecilia BeatrizC ELEGANSMYASTHENIC SYNDROMESPATCH-CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The free-living nematode Caenorhabditis elegans is a model for the study of human neurological diseases and drug testing. In humans, gain-of-function mutations in muscle nicotinic receptor (AChR) subunits lead to slow-channel congenital myasthenic syndromes. We here explored if homologous mutations in C. elegans subunits mimic the molecular and functional changes observed in patients. In the essential UNC-38 and UNC-29 subunits of the levamisole-sensitive AChR (L-AChR) we mutated residues at position 9’ of M2, which forms the gate of the channel, and position 12’, which mimics a mutation found in a patient. We generated transgenic worms expressing the mutant AChRs in muscle using both wild-type and null-mutant strains as backgrounds. Electrophysiological studies show a dramatic increase (14-fold) in the open duration of L-AChR channels, and a decrease in the desensitization rate of macroscopic currents elicited by ACh, similarly to the changes detected in human mutant AChRs. Unexpectedly, no significant changes in locomotion and levamisole-sensitivity of transgenic worms occur. Overall, our results show that mutant subunits are incorporated into functional L-AChRs and lead to kinetic changes similar to those observed in vertebrate AChRs, thus revealing a high degree of conservation of functional roles of amino acids between C. elegans and human AChRs. These results open doors for establishing C. elegans models for human myasthenic syndromes.Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Hernando, Guillermina Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaXXVIII Reunión Anual de la Sociedad Argentina de Investigación en NeurocienciasHuerta GrandeArgentinaSociedad Argentina de Investigación en NeurocienciasSociedad Argentina de Investigación en Neurociencias2013info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/235311Establishing C. elegans models of human congenital myasthenic syndromes; XXVIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Huerta Grande; Argentina; 2013; 289-289CONICET DigitalCONICETengNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:55:16Zoai:ri.conicet.gov.ar:11336/235311instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-11-12 09:55:17.22CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Establishing C. elegans models of human congenital myasthenic syndromes
title Establishing C. elegans models of human congenital myasthenic syndromes
spellingShingle Establishing C. elegans models of human congenital myasthenic syndromes
Bergé, Ignacio
C ELEGANS
MYASTHENIC SYNDROMES
PATCH-CLAMP
title_short Establishing C. elegans models of human congenital myasthenic syndromes
title_full Establishing C. elegans models of human congenital myasthenic syndromes
title_fullStr Establishing C. elegans models of human congenital myasthenic syndromes
title_full_unstemmed Establishing C. elegans models of human congenital myasthenic syndromes
title_sort Establishing C. elegans models of human congenital myasthenic syndromes
dc.creator.none.fl_str_mv Bergé, Ignacio
Hernando, Guillermina Silvana
Bouzat, Cecilia Beatriz
author Bergé, Ignacio
author_facet Bergé, Ignacio
Hernando, Guillermina Silvana
Bouzat, Cecilia Beatriz
author_role author
author2 Hernando, Guillermina Silvana
Bouzat, Cecilia Beatriz
author2_role author
author
dc.subject.none.fl_str_mv C ELEGANS
MYASTHENIC SYNDROMES
PATCH-CLAMP
topic C ELEGANS
MYASTHENIC SYNDROMES
PATCH-CLAMP
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The free-living nematode Caenorhabditis elegans is a model for the study of human neurological diseases and drug testing. In humans, gain-of-function mutations in muscle nicotinic receptor (AChR) subunits lead to slow-channel congenital myasthenic syndromes. We here explored if homologous mutations in C. elegans subunits mimic the molecular and functional changes observed in patients. In the essential UNC-38 and UNC-29 subunits of the levamisole-sensitive AChR (L-AChR) we mutated residues at position 9’ of M2, which forms the gate of the channel, and position 12’, which mimics a mutation found in a patient. We generated transgenic worms expressing the mutant AChRs in muscle using both wild-type and null-mutant strains as backgrounds. Electrophysiological studies show a dramatic increase (14-fold) in the open duration of L-AChR channels, and a decrease in the desensitization rate of macroscopic currents elicited by ACh, similarly to the changes detected in human mutant AChRs. Unexpectedly, no significant changes in locomotion and levamisole-sensitivity of transgenic worms occur. Overall, our results show that mutant subunits are incorporated into functional L-AChRs and lead to kinetic changes similar to those observed in vertebrate AChRs, thus revealing a high degree of conservation of functional roles of amino acids between C. elegans and human AChRs. These results open doors for establishing C. elegans models for human myasthenic syndromes.
Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Hernando, Guillermina Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
XXVIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias
Huerta Grande
Argentina
Sociedad Argentina de Investigación en Neurociencias
description The free-living nematode Caenorhabditis elegans is a model for the study of human neurological diseases and drug testing. In humans, gain-of-function mutations in muscle nicotinic receptor (AChR) subunits lead to slow-channel congenital myasthenic syndromes. We here explored if homologous mutations in C. elegans subunits mimic the molecular and functional changes observed in patients. In the essential UNC-38 and UNC-29 subunits of the levamisole-sensitive AChR (L-AChR) we mutated residues at position 9’ of M2, which forms the gate of the channel, and position 12’, which mimics a mutation found in a patient. We generated transgenic worms expressing the mutant AChRs in muscle using both wild-type and null-mutant strains as backgrounds. Electrophysiological studies show a dramatic increase (14-fold) in the open duration of L-AChR channels, and a decrease in the desensitization rate of macroscopic currents elicited by ACh, similarly to the changes detected in human mutant AChRs. Unexpectedly, no significant changes in locomotion and levamisole-sensitivity of transgenic worms occur. Overall, our results show that mutant subunits are incorporated into functional L-AChRs and lead to kinetic changes similar to those observed in vertebrate AChRs, thus revealing a high degree of conservation of functional roles of amino acids between C. elegans and human AChRs. These results open doors for establishing C. elegans models for human myasthenic syndromes.
publishDate 2013
dc.date.none.fl_str_mv 2013
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/235311
Establishing C. elegans models of human congenital myasthenic syndromes; XXVIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Huerta Grande; Argentina; 2013; 289-289
CONICET Digital
CONICET
url http://hdl.handle.net/11336/235311
identifier_str_mv Establishing C. elegans models of human congenital myasthenic syndromes; XXVIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Huerta Grande; Argentina; 2013; 289-289
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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application/pdf
application/pdf
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Investigación en Neurociencias
publisher.none.fl_str_mv Sociedad Argentina de Investigación en Neurociencias
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.24909

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