Increased translation as a novel pathogenic mechanism in Huntington's disease

Huntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene. Striatal projection neurons are mainly affected, leading to motor symptoms, but molecular mechanisms involved in their vulnerability are not fully characterized. Here, we show...

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Autores: Creus Muncunill, Jordi, Badillos Rodríguez, Raquel, Garcia-Forn, Marta, Masana Nadal, Mercè, García-Díaz Barriga, Gerardo, Guisado Corcoll, Anna, Alberch i Vié, Jordi, 1959-, Malagelada Grau, Cristina, Delgado García, José M., Gruart i Massó, Agnès, Pérez Navarro, Esther
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/184510
Acceso en línea:https://hdl.handle.net/2445/184510
Access Level:acceso abierto
Palabra clave:Corea de Huntington
Proteïnes
Depressió psíquica
Síntesi proteica
Huntington's chorea
Proteins
Mental depression
Protein synthesis
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spelling Increased translation as a novel pathogenic mechanism in Huntington's diseaseCreus Muncunill, JordiBadillos Rodríguez, RaquelGarcia-Forn, MartaMasana Nadal, MercèGarcía-Díaz Barriga, GerardoGuisado Corcoll, AnnaAlberch i Vié, Jordi, 1959-Malagelada Grau, CristinaDelgado García, José M.Gruart i Massó, AgnèsPérez Navarro, EstherCorea de HuntingtonProteïnesDepressió psíquicaSíntesi proteicaHuntington's choreaProteinsMental depressionProtein synthesisHuntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene. Striatal projection neurons are mainly affected, leading to motor symptoms, but molecular mechanisms involved in their vulnerability are not fully characterized. Here, we show that eIF4E binding protein (4E-BP), a protein that inhibits translation, is inactivated in Huntington's disease striatum by increased phosphorylation. Accordingly, we detected aberrant de novo protein synthesis. Proteomic characterization indicates that translation specifically affects sets of proteins as we observed upregulation of ribosomal and oxidative phosphorylation proteins and downregulation of proteins related to neuronal structure and function. Interestingly, treatment with the translation inhibitor 4EGI-1 prevented R6/1 mice motor deficits, although corticostriatal long-term depression was not markedly changed in behaving animals. At the molecular level, injection of 4EGI-1 normalized protein synthesis and ribosomal content in R6/1 mouse striatum. In conclusion, our results indicate that dysregulation of protein synthesis is involved in mutant huntingtin-induced striatal neuron dysfunction.Oxford University Press2022202220192022info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion18 p.application/pdfhttps://hdl.handle.net/2445/184510Articles publicats en revistes (Biomedicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1093/brain/awz230Brain, 2019, vol. 142, num. 10, p. 3158-3175https://doi.org/10.1093/brain/awz230(c) Creus Muncunill, Jordi et al., 2019info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1845102026-05-29T05:05:01Z
dc.title.none.fl_str_mv Increased translation as a novel pathogenic mechanism in Huntington's disease
title Increased translation as a novel pathogenic mechanism in Huntington's disease
spellingShingle Increased translation as a novel pathogenic mechanism in Huntington's disease
Creus Muncunill, Jordi
Corea de Huntington
Proteïnes
Depressió psíquica
Síntesi proteica
Huntington's chorea
Proteins
Mental depression
Protein synthesis
title_short Increased translation as a novel pathogenic mechanism in Huntington's disease
title_full Increased translation as a novel pathogenic mechanism in Huntington's disease
title_fullStr Increased translation as a novel pathogenic mechanism in Huntington's disease
title_full_unstemmed Increased translation as a novel pathogenic mechanism in Huntington's disease
title_sort Increased translation as a novel pathogenic mechanism in Huntington's disease
dc.creator.none.fl_str_mv Creus Muncunill, Jordi
Badillos Rodríguez, Raquel
Garcia-Forn, Marta
Masana Nadal, Mercè
García-Díaz Barriga, Gerardo
Guisado Corcoll, Anna
Alberch i Vié, Jordi, 1959-
Malagelada Grau, Cristina
Delgado García, José M.
Gruart i Massó, Agnès
Pérez Navarro, Esther
author Creus Muncunill, Jordi
author_facet Creus Muncunill, Jordi
Badillos Rodríguez, Raquel
Garcia-Forn, Marta
Masana Nadal, Mercè
García-Díaz Barriga, Gerardo
Guisado Corcoll, Anna
Alberch i Vié, Jordi, 1959-
Malagelada Grau, Cristina
Delgado García, José M.
Gruart i Massó, Agnès
Pérez Navarro, Esther
author_role author
author2 Badillos Rodríguez, Raquel
Garcia-Forn, Marta
Masana Nadal, Mercè
García-Díaz Barriga, Gerardo
Guisado Corcoll, Anna
Alberch i Vié, Jordi, 1959-
Malagelada Grau, Cristina
Delgado García, José M.
Gruart i Massó, Agnès
Pérez Navarro, Esther
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Corea de Huntington
Proteïnes
Depressió psíquica
Síntesi proteica
Huntington's chorea
Proteins
Mental depression
Protein synthesis
topic Corea de Huntington
Proteïnes
Depressió psíquica
Síntesi proteica
Huntington's chorea
Proteins
Mental depression
Protein synthesis
description Huntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene. Striatal projection neurons are mainly affected, leading to motor symptoms, but molecular mechanisms involved in their vulnerability are not fully characterized. Here, we show that eIF4E binding protein (4E-BP), a protein that inhibits translation, is inactivated in Huntington's disease striatum by increased phosphorylation. Accordingly, we detected aberrant de novo protein synthesis. Proteomic characterization indicates that translation specifically affects sets of proteins as we observed upregulation of ribosomal and oxidative phosphorylation proteins and downregulation of proteins related to neuronal structure and function. Interestingly, treatment with the translation inhibitor 4EGI-1 prevented R6/1 mice motor deficits, although corticostriatal long-term depression was not markedly changed in behaving animals. At the molecular level, injection of 4EGI-1 normalized protein synthesis and ribosomal content in R6/1 mouse striatum. In conclusion, our results indicate that dysregulation of protein synthesis is involved in mutant huntingtin-induced striatal neuron dysfunction.
publishDate 2019
dc.date.none.fl_str_mv 2019
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/184510
url https://hdl.handle.net/2445/184510
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1093/brain/awz230
Brain, 2019, vol. 142, num. 10, p. 3158-3175
https://doi.org/10.1093/brain/awz230
dc.rights.none.fl_str_mv (c) Creus Muncunill, Jordi et al., 2019
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Creus Muncunill, Jordi et al., 2019
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 18 p.
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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