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This 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). AG was supported by grants from MICIU/AEI/10.13039/501100011033 and by European Union NextGenerationEU/PRTR (grant CNS2022 - 135391, "Consolidacion" program), and by the Fundacion Ramon Areces (grant CIVP21A7024). JS-B was supported by a FPU grant from the Spanish Ministry of Science and Innovation (grant #FPU18/00194). PG-S was supported by a FPU grant from the Spanish Ministry of Science and Innovation (grant #FPU21/02928). GC-C was funded by a FI-2021 grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (grant #FI-B-00378). AC-G was supported by a Michael J. Fox Foundation grant (MJFF-000858). C.M, J.A., A.G., E.M and E.P-N, are also supported by AGAUR, Generalitat de Catalunya grant # 2021 SGR 01086. Also, the project has been supported by Maria de Maeztu Unit of Excellent, Institute of Neurosciences, University of Barcelona, MDM-2017-0729, Ministry of Science, Innovation, and Universities. Funding for open access charge: CIBERNED and Universitat de Barcelona.

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

Publicated to:Nucleic Acids Research. 52 (18): 11158-11176 - 2024-09-12 52(18), DOI: 10.1093/nar/gkae776

Authors: Campoy-Campos, Genis; Solana-Balaguer, Julia; Guisado-Corcoll, Anna; Chicote-Gonzalez, Almudena; Garcia-Segura, Pol; Perez-Sisques, Leticia; Torres, Adrian Gabriel; Canal, Merce; Molina-Porcel, Laura; Fernandez-Irigoyen, Joaquin; Santamaria, Enrique; de Pouplana, Lluis Ribas; Alberch, Jordi; Marti, Eulalia; Giralt, Albert; Perez-Navarro, Esther; Malagelada, Cristina

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Abstract

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. Graphical Abstract

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