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

Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in (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 doma...

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Published in:Science advances 2023-11, Vol.9 (45), p.eadf7997-eadf7997
Main Authors: 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, Ichida, Justin K, Pandey, Udai B, Wolin, Sandra L, Stupp, Samuel I, Kiskinis, Evangelos
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis - genetics
Animals
C9orf72 Protein - genetics
C9orf72 Protein - metabolism
Cellular Neuroscience
Chromatin Immunoprecipitation Sequencing
Diseases and Disorders
DNA Repeat Expansion
Drosophila - genetics
Drosophila - metabolism
Frontotemporal Dementia - genetics
Humans
Neuroscience
RNA - genetics
RNA, Ribosomal - genetics
SciAdv r-articles
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Summary:Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in (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 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adf7997