CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against <i>C9ORF72</i> ALS/FTD poly-GR pathophysiology

Ortega, Juan A. ; 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) ; Ichida, Justin K. ; Pandey, Udai B. ; Wolin, Sandra L. ; Stupp, Samuel I. ; Kiskinis, Evangelos

Resumen: 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.

Idioma: Inglés

DOI: 10.1126/sciadv.adf7997

Año: 2023

Publicado en: Science advances 9, 45 (2023)
ISSN: 2375-2548

Factor impacto JCR: 11.7 (2023)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 11 / 134 = 0.082 (2023) - Q1 - T1

Factor impacto CITESCORE: 21.4 - Multidisciplinary (Q1)

Factor impacto SCIMAGO: 4.483 - Multidisciplinary (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Estadís. Investig. Opera. (Dpto. Métodos Estadísticos)