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

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dc.contributor.authorCampoy-Campos, Genís
dc.contributor.authorSolana-Balaguer, Júlia
dc.contributor.authorGuisado-Corcoll, Anna
dc.contributor.authorChicote-González, Almudena
dc.contributor.authorGarcía-Segura, Pol
dc.contributor.authorPérez-Sisqués, Leticia
dc.contributor.authorGabriel Torres, Adrián
dc.contributor.authorCanal, Mercè
dc.contributor.authorMolina-Porcel, Laura
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorPouplana, Lluís Ribas de
dc.contributor.authorAlberch, Jordi
dc.contributor.authorMartí, Eulàlia
dc.contributor.authorGiralt, Albert
dc.contributor.authorPérez-Navarro, Esther
dc.contributor.authorMalagelada, Cristina
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2025-02-07T12:12:04Z
dc.date.available2025-02-07T12:12:04Z
dc.date.issued2024-09-12
dc.date.updated2025-02-07T12:06:01Z
dc.description.abstractRTP801/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.en
dc.description.sponsorshipThis work was supported in part by the grants SAF2017-88812-R and PID2020-119236RB-I00 by MICIU/AEI/10.13039/501100011033 and by 'ERDF A way of making Europe' (from CM), PID2020-119386RB-I00 (from JA), PID2019-106447RB-I00 (from EP-N), PID2020- 113953RB-I00 (from EM), and PID2019-110356RB-I00 (from JF-I and ES).
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dc.identifier.citationCampoy-Campos, G., Solana-Balaguer, J., Guisado-Corcoll, A., Chicote-González, A., Garcia-Segura, P., Pérez-Sisqués, L., Torres, A. G., Canal, M., Molina-Porcel, L., Fernández-Irigoyen, J., Santamaria, E., De Pouplana, L. R., Alberch, J., Martí, E., Giralt, A., Pérez-Navarro, E., Malagelada, C. (2024). RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease. Nucleic Acids Research, 52(18), 11158-11176. https://doi.org/10.1093/nar/gkae776.
dc.identifier.doi10.1093/nar/gkae776
dc.identifier.issn0305-1048
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/53319
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.ispartofNucleic Acids Research (2024), vol. 52, núm. 18
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-88812-R/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119236RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119386RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106447RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-113953RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110356RB-I00/ES/
dc.relation.publisherversionhttps://doi.org/10.1093/nar/gkae776
dc.rights© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectRTP801/REDD1en
dc.subjectNeurodegenerationen
dc.subjecttRNA ligase complex (tRNA-LC) interactionen
dc.subjectXBP1 splicingen
dc.subjectUnfolded Protein Response (UPR)en
dc.subjectAlzheimer's disease therapeutic targetsen
dc.titleRTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's diseaseen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscoveryabacfd17-2b93-4d99-bae2-52053d57401e

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