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

Autor: Ortega JA; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.; Department of Pathology and Experimental Therapy, Institute of Neurosciences, University of Barcelona, Barcelona 08907, Spain., Sasselli IR; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA.; Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia-San Sebastián 20014, Spain.; Centro de Fisica de Materiales (CFM), CSIC-UPV/EHU, 20018 San Sebastián, Spain., Boccitto M; RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Fleming AC; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Fortuna TR; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Li Y; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Sato K; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA., Clemons TD; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA., Mckenna ED; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Nguyen TP; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Anderson EN; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Asin J; Department of Statistical Methods, School of Engineering, University of Zaragoza, Zaragoza 50018, Spain., Ichida JK; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Pandey UB; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Wolin SL; RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Stupp SI; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA.; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.; Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.; Department of Medicine, Northwestern University, Chicago, IL 60611, USA., Kiskinis E; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA.; Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Nov 10; Vol. 9 (45), pp. eadf7997. Date of Electronic Publication: 2023 Nov 10.
DOI: 10.1126/sciadv.adf7997
Abstrakt: 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.
Databáze: MEDLINE