RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease

Campoy Campos, Genís; Solana Balaguer, Júlia; Guisado Corcoll, Anna; Chicote González, Almudena; García Segura, Pol; Pérez Sisqués, Leticia; Gabriel Torres, Adrián; Canal de la Iglesia, Mercè; Molina Porcel, Laura; Fernández Irigoyen, Joaquín; Santamaría, Enrique; Ribas de Pouplana, Lluís; Alberch i Vié, Jordi, 1959-; Martí Puig, Eulàlia; Giralt Torroella, Albert; Pérez Navarro, Esther; Malagelada Grau, Cristina

RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease

RTP801/REDD1 is a stress-responsive protein overexpressed in neurodegenerative diseases such as Alzheimer’s disease (AD) that contributes to cognitive deficits and neuroinflammation. Here, we found that RTP801 interacts with HSPC117, DDX1 and CGI-99, three members of the tRNA ligase complex (tRNA-LC...

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Autores:	Campoy Campos, Genís, Solana Balaguer, Júlia, Guisado Corcoll, Anna, Chicote González, Almudena, García Segura, Pol, Pérez Sisqués, Leticia, Gabriel Torres, Adrián, Canal de la Iglesia, Mercè, Molina Porcel, Laura, Fernández Irigoyen, Joaquín, Santamaría, Enrique, Ribas de Pouplana, Lluís, Alberch i Vié, Jordi, 1959-, Martí Puig, Eulàlia, Giralt Torroella, Albert, Pérez Navarro, Esther, Malagelada Grau, Cristina
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2024
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:2445/222795
Acceso en línea:	https://hdl.handle.net/2445/222795
Access Level:	acceso abierto
Palabra clave:	Malalties neurodegeneratives Neurobiologia molecular Neurodegenerative Diseases Molecular neurobiology

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spelling	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's diseaseCampoy Campos, GenísSolana Balaguer, JúliaGuisado Corcoll, AnnaChicote González, AlmudenaGarcía Segura, PolPérez Sisqués, LeticiaGabriel Torres, AdriánCanal de la Iglesia, MercèMolina Porcel, LauraFernández Irigoyen, JoaquínSantamaría, EnriqueRibas de Pouplana, LluísAlberch i Vié, Jordi, 1959-Martí Puig, EulàliaGiralt Torroella, AlbertPérez Navarro, EstherMalagelada Grau, CristinaMalalties neurodegenerativesNeurobiologia molecularNeurodegenerative DiseasesMolecular neurobiologyRTP801/REDD1 is a stress-responsive protein overexpressed in neurodegenerative diseases such as Alzheimer’s disease (AD) that contributes to cognitive deficits and neuroinflammation. Here, we found that RTP801 interacts with HSPC117, DDX1 and CGI-99, three members of the tRNA ligase complex (tRNA-LC), which ligates the excised exons of intron-containing tRNAs and the mRNA exons of the transcription factor XBP1 during the unfolded protein response (UPR). We also found that RTP801 modulates the mRNA ligase activity of the complex in vitro since RTP801 knockdown promoted XBP1 splicing and the expression of its transcriptional target, SEC24D. Conversely, RTP801 overexpression inhibited the splicing of XBP1. Similarly, in human AD postmortem hippocampal samples, where RTP801 is upregulated, we found that XBP1 splicing was dramatically decreased. In the 5xFAD mouse model of AD, silencing RTP801 expression in hippocampal neurons promoted Xbp1 splicing and prevented the accumulation of intron-containing pre-tRNAs. Finally, the tRNA-enriched fraction obtained from 5xFAD mice promoted abnormal dendritic arborization in cultured hippocampal neurons, and RTP801 silencing in the source neurons prevented this phenotype. Altogether, these results show that elevated RTP801 impairs RNA processing in vitro and in vivo in the context of AD and suggest that RTP801 inhibition could be a promising therapeutic approach.Oxford University Press2025202520242025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion19 p.application/pdfhttps://hdl.handle.net/2445/222795Articles 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)InglésReproducció del document publicat a: https://doi.org/10.1093/nar/gkae776Nucleic Acids Research, 2024, vol. 52, num.18, p. 11158-11176https://doi.org/10.1093/nar/gkae776cc-by (c) Campoy-Campos G et al., 2024http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2227952026-05-29T05:05:01Z
dc.title.none.fl_str_mv	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
title	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
spellingShingle	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease Campoy Campos, Genís Malalties neurodegeneratives Neurobiologia molecular Neurodegenerative Diseases Molecular neurobiology
title_short	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
title_full	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
title_fullStr	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
title_full_unstemmed	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
title_sort	RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
dc.creator.none.fl_str_mv	Campoy Campos, Genís Solana Balaguer, Júlia Guisado Corcoll, Anna Chicote González, Almudena García Segura, Pol Pérez Sisqués, Leticia Gabriel Torres, Adrián Canal de la Iglesia, Mercè Molina Porcel, Laura Fernández Irigoyen, Joaquín Santamaría, Enrique Ribas de Pouplana, Lluís Alberch i Vié, Jordi, 1959- Martí Puig, Eulàlia Giralt Torroella, Albert Pérez Navarro, Esther Malagelada Grau, Cristina
author	Campoy Campos, Genís
author_facet	Campoy Campos, Genís Solana Balaguer, Júlia Guisado Corcoll, Anna Chicote González, Almudena García Segura, Pol Pérez Sisqués, Leticia Gabriel Torres, Adrián Canal de la Iglesia, Mercè Molina Porcel, Laura Fernández Irigoyen, Joaquín Santamaría, Enrique Ribas de Pouplana, Lluís Alberch i Vié, Jordi, 1959- Martí Puig, Eulàlia Giralt Torroella, Albert Pérez Navarro, Esther Malagelada Grau, Cristina
author_role	author
author2	Solana Balaguer, Júlia Guisado Corcoll, Anna Chicote González, Almudena García Segura, Pol Pérez Sisqués, Leticia Gabriel Torres, Adrián Canal de la Iglesia, Mercè Molina Porcel, Laura Fernández Irigoyen, Joaquín Santamaría, Enrique Ribas de Pouplana, Lluís Alberch i Vié, Jordi, 1959- Martí Puig, Eulàlia Giralt Torroella, Albert Pérez Navarro, Esther Malagelada Grau, Cristina
author2_role	author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Malalties neurodegeneratives Neurobiologia molecular Neurodegenerative Diseases Molecular neurobiology
topic	Malalties neurodegeneratives Neurobiologia molecular Neurodegenerative Diseases Molecular neurobiology
description	RTP801/REDD1 is a stress-responsive protein overexpressed in neurodegenerative diseases such as Alzheimer’s disease (AD) that contributes to cognitive deficits and neuroinflammation. Here, we found that RTP801 interacts with HSPC117, DDX1 and CGI-99, three members of the tRNA ligase complex (tRNA-LC), which ligates the excised exons of intron-containing tRNAs and the mRNA exons of the transcription factor XBP1 during the unfolded protein response (UPR). We also found that RTP801 modulates the mRNA ligase activity of the complex in vitro since RTP801 knockdown promoted XBP1 splicing and the expression of its transcriptional target, SEC24D. Conversely, RTP801 overexpression inhibited the splicing of XBP1. Similarly, in human AD postmortem hippocampal samples, where RTP801 is upregulated, we found that XBP1 splicing was dramatically decreased. In the 5xFAD mouse model of AD, silencing RTP801 expression in hippocampal neurons promoted Xbp1 splicing and prevented the accumulation of intron-containing pre-tRNAs. Finally, the tRNA-enriched fraction obtained from 5xFAD mice promoted abnormal dendritic arborization in cultured hippocampal neurons, and RTP801 silencing in the source neurons prevented this phenotype. Altogether, these results show that elevated RTP801 impairs RNA processing in vitro and in vivo in the context of AD and suggest that RTP801 inhibition could be a promising therapeutic approach.
publishDate	2024
dc.date.none.fl_str_mv	2024 2025 2025 2025
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/2445/222795
url	https://hdl.handle.net/2445/222795
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1093/nar/gkae776 Nucleic Acids Research, 2024, vol. 52, num.18, p. 11158-11176 https://doi.org/10.1093/nar/gkae776
dc.rights.none.fl_str_mv	cc-by (c) Campoy-Campos G et al., 2024 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc-by (c) Campoy-Campos G et al., 2024 http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	19 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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RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease

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