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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Detalles Bibliográficos
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:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu: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
Descripción
Sumario: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.

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