000131283 001__ 131283
000131283 005__ 20241125101123.0
000131283 0247_ $$2doi$$a10.1126/sciadv.adf7997
000131283 0248_ $$2sideral$$a136745
000131283 037__ $$aART-2023-136745
000131283 041__ $$aeng
000131283 100__ $$aOrtega, Juan A.
000131283 245__ $$aCLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against <i>C9ORF72</i> ALS/FTD poly-GR pathophysiology
000131283 260__ $$c2023
000131283 5060_ $$aAccess copy available to the general public$$fUnrestricted
000131283 5203_ $$aAmyotrophic 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.
000131283 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000131283 590__ $$a11.7$$b2023
000131283 592__ $$a4.483$$b2023
000131283 591__ $$aMULTIDISCIPLINARY SCIENCES$$b11 / 134 = 0.082$$c2023$$dQ1$$eT1
000131283 593__ $$aMultidisciplinary$$c2023$$dQ1
000131283 594__ $$a21.4$$b2023
000131283 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000131283 700__ $$aSasselli, Ivan R.
000131283 700__ $$aBoccitto, Marco
000131283 700__ $$aFleming, Andrew C.
000131283 700__ $$aFortuna, Tyler R.
000131283 700__ $$aLi, Yichen
000131283 700__ $$aSato, Kohei
000131283 700__ $$aClemons, Tristan D.
000131283 700__ $$aMckenna, Elizabeth D.
000131283 700__ $$aNguyen, Thao P.
000131283 700__ $$aAnderson, Eric N.
000131283 700__ $$0(orcid)0000-0002-0174-789X$$aAsin, Jesus$$uUniversidad de Zaragoza
000131283 700__ $$aIchida, Justin K.
000131283 700__ $$aPandey, Udai B.
000131283 700__ $$aWolin, Sandra L.
000131283 700__ $$aStupp, Samuel I.
000131283 700__ $$aKiskinis, Evangelos
000131283 7102_ $$12007$$2265$$aUniversidad de Zaragoza$$bDpto. Métodos Estadísticos$$cÁrea Estadís. Investig. Opera.
000131283 773__ $$g9, 45 (2023)$$pSci. adv.$$tScience advances$$x2375-2548
000131283 8564_ $$s2932548$$uhttps://zaguan.unizar.es/record/131283/files/texto_completo.pdf$$yVersión publicada
000131283 8564_ $$s3722063$$uhttps://zaguan.unizar.es/record/131283/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000131283 909CO $$ooai:zaguan.unizar.es:131283$$particulos$$pdriver
000131283 951__ $$a2024-11-22-11:56:57
000131283 980__ $$aARTICLE