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), 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.
Authors
- Albert Giralt (ORCID: https://orcid.org/0000-0001-5334-0963)
- Laura Molina‐Porcel (ORCID: https://orcid.org/0000-0003-4068-8578)
- Almudena Chicote‐González (ORCID: https://orcid.org/0009-0009-5459-1065)
- Jordi Alberch (ORCID: https://orcid.org/0000-0002-8684-2721)
- Esther Pérez‐Navarro (ORCID: https://orcid.org/0000-0001-9165-6539)
- Eulàlia Martı́ (ORCID: https://orcid.org/0000-0002-1030-3158)
- Leticia Pérez‐Sisqués (ORCID: https://orcid.org/0000-0002-9682-9811)
- Cristina Malagelada (ORCID: https://orcid.org/0000-0001-7185-436X)
- Pol Garcia‐Segura (ORCID: https://orcid.org/0000-0002-0169-824X)
- Júlia Solana‐Balaguer (ORCID: https://orcid.org/0000-0002-2263-0092)
- Genís Campoy‐Campos (ORCID: https://orcid.org/0000-0002-4235-7628)
- Lluı́s Ribas de Pouplana (ORCID: https://orcid.org/0000-0002-2087-0359)
- Adrián Gabriel Torres (ORCID: https://orcid.org/0000-0002-5479-1325)
- Anna Guisado-Corcoll (ORCID: https://orcid.org/0000-0002-8521-386X)
- Enrique Santamaría (ORCID: https://orcid.org/0000-0001-8046-8102)
- Joaquín Fernández‐Irigoyen (ORCID: https://orcid.org/0000-0001-5072-4099)
- Mercè Canal
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Hospital Clínic de Barcelona (ES)
- Navarrabiomed (ES)
- Institute for Research in Biomedicine (ES)
- Barcelona Institute of Science and Technology (ES)
- Departamento de Salud (ES)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2024-09-12
- DOI
- https://doi.org/10.1093/nar/gkae776
- Citations
- 4
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Fundación Ramón Areces
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Universitat de Barcelona
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- European Regional Development Fund
- Agencia Estatal de Investigación