Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/222795
Title: RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease<strong></strong>
Author: 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-
Marti Puig, Eulalia
Giralt Torroella, Albert
Pérez Navarro, Esther
Malagelada Grau, Cristina
Keywords: Malalties neurodegeneratives
Neurobiologia molecular
Neurodegenerative Diseases
Molecular neurobiology
Issue Date: 14-Oct-2024
Publisher: Oxford University Press
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.
Note: Reproducció del document publicat a: https://doi.org/10.1093/nar/gkae776
It is part of: Nucleic Acids Research, 2024, vol. 52, num.18, p. 11158-11176
URI: https://hdl.handle.net/2445/222795
Related resource: https://doi.org/10.1093/nar/gkae776
ISSN: 0305-1048
Appears in Collections:Articles publicats en revistes (Biomedicina)

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