A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutan...

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Autores: Bañez-Coronel, Mónica, Porta, Sílvia, Kagerbauer, Birgit, Mateu Huertas, Elisabet, Pantano, Lorena, Ferrer, Isidro (Ferrer Abizanda), Guzmán, Manuel, Estivill, Xavier, 1955-, Martí Puig, Eulàlia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/49112
Acceso en línea:https://hdl.handle.net/2445/49112
Access Level:acceso abierto
Palabra clave:Corea de Huntington
Pèptids
Teixit nerviós
Neurotoxines
Huntington's chorea
Peptides
Nerve tissue
Neurotoxins
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spelling A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activityBañez-Coronel, MónicaPorta, SílviaKagerbauer, BirgitMateu Huertas, ElisabetPantano, LorenaFerrer, Isidro (Ferrer Abizanda)Guzmán, ManuelEstivill, Xavier, 1955-Martí Puig, EulàliaCorea de HuntingtonPèptidsTeixit nerviósNeurotoxinesHuntington's choreaPeptidesNerve tissueNeurotoxinsHuntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approachesPublic Library of Science (PLoS)2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/49112Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1002481PLoS Genetics, 2012, vol. 8, num. 2, e1002481http://dx.doi.org/10.1371/journal.pgen.1002481cc-by (c) Bañez-Coronel, M. et al., 2012http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/491122026-05-27T06:46:51Z
dc.title.none.fl_str_mv A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
title A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
spellingShingle A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
Bañez-Coronel, Mónica
Corea de Huntington
Pèptids
Teixit nerviós
Neurotoxines
Huntington's chorea
Peptides
Nerve tissue
Neurotoxins
title_short A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
title_full A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
title_fullStr A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
title_full_unstemmed A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
title_sort A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
dc.creator.none.fl_str_mv Bañez-Coronel, Mónica
Porta, Sílvia
Kagerbauer, Birgit
Mateu Huertas, Elisabet
Pantano, Lorena
Ferrer, Isidro (Ferrer Abizanda)
Guzmán, Manuel
Estivill, Xavier, 1955-
Martí Puig, Eulàlia
author Bañez-Coronel, Mónica
author_facet Bañez-Coronel, Mónica
Porta, Sílvia
Kagerbauer, Birgit
Mateu Huertas, Elisabet
Pantano, Lorena
Ferrer, Isidro (Ferrer Abizanda)
Guzmán, Manuel
Estivill, Xavier, 1955-
Martí Puig, Eulàlia
author_role author
author2 Porta, Sílvia
Kagerbauer, Birgit
Mateu Huertas, Elisabet
Pantano, Lorena
Ferrer, Isidro (Ferrer Abizanda)
Guzmán, Manuel
Estivill, Xavier, 1955-
Martí Puig, Eulàlia
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Corea de Huntington
Pèptids
Teixit nerviós
Neurotoxines
Huntington's chorea
Peptides
Nerve tissue
Neurotoxins
topic Corea de Huntington
Pèptids
Teixit nerviós
Neurotoxines
Huntington's chorea
Peptides
Nerve tissue
Neurotoxins
description Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches
publishDate 2012
dc.date.none.fl_str_mv 2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/49112
url https://hdl.handle.net/2445/49112
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1002481
PLoS Genetics, 2012, vol. 8, num. 2, e1002481
http://dx.doi.org/10.1371/journal.pgen.1002481
dc.rights.none.fl_str_mv cc-by (c) Bañez-Coronel, M. et al., 2012
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Bañez-Coronel, M. et al., 2012
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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