131283 20241125101123.0 doi 10.1126/sciadv.adf7997 sideral 136745 ART-2023-136745 eng Ortega, Juan A. CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against <i>C9ORF72</i> ALS/FTD poly-GR pathophysiology 2023 Access copy available to the general public Unrestricted Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear. Here, we used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA “bait” oligonucleotides restore poly-GR–associated ribosomal deficits and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal dysfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms. info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 11.7 2023 MULTIDISCIPLINARY SCIENCES 11 / 134 = 0.082 2023 Q1 T1 4.483 2023 Multidisciplinary 2023 Q1 21.4 2023 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Sasselli, Ivan R. Boccitto, Marco Fleming, Andrew C. Fortuna, Tyler R. Li, Yichen Sato, Kohei Clemons, Tristan D. Mckenna, Elizabeth D. Nguyen, Thao P. Anderson, Eric N. Asin, Jesus Universidad de Zaragoza (orcid)0000-0002-0174-789X Ichida, Justin K. Pandey, Udai B. Wolin, Sandra L. Stupp, Samuel I. Kiskinis, Evangelos 2007 265 Universidad de Zaragoza Dpto. Métodos Estadísticos Área Estadís. Investig. Opera. 9, 45 (2023) Sci. adv. Science advances 2375-2548 2932548 http://zaguan.unizar.es/record/131283/files/texto_completo.pdf Versión publicada 3722063 http://zaguan.unizar.es/record/131283/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:131283 articulos driver 2024-11-22-11:56:57 ARTICLE