Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats

Magdalena Derbis, Emre Kul, Daria Niewiadomska, Michał Sekrecki, Agnieszka Piasecka, Katarzyna Taylor, Renate K. Hukema, Oliver Stork, Krzysztof Sobczak*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)


Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.

Original languageEnglish
Article number1265
JournalNature Communications
Issue number1
Publication statusPublished - 24 Feb 2021

Bibliographical note

Funding Information:
The authors wish to thank Nicolas Charlet-Berguerand for providing 8FM; anti-FMRpolyG antibody and 20xCGG, 60xCGG, and 100xCGG genetic constructs, Anita Bhattacharyya for providing C0603, FX11-02, and WC26 fibroblasts and Paul J. Hagerman for providing C6 and F3 fibroblasts. This work was supported by the National Centre for Research and Development grant ERA-NET-E-Rare-2/III/DRUG_FX-SPREMUT/01/2016 (to K.S.), by the Ministry of Science and Higher Education of the Republic of Poland, from the quality-promoting subsidy, under the Leading National Research Centre (KNOW) program for the years 2012-2017 [KNOW RNA Research Centre in Poznan (No. 01/KNOW2/2014)], by the Foundation for Polish Science, TEAM POIR.04.04.00-00-5C0C/17-00 (to K.S.), by the Initiative of Excellence–Research University (05/IDUB/2019/94) at Adam Mickiewicz University, Poznan, Poland, and from the Poznan RNA Research Centre (to K.S.), by ERA-Net for Research Programmes on Rare Diseases grant 01GM1505 “Drug_FXSPreMut” (E-Rare-2 JTC 2014; to O.S.) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 362321501/RTG 2413 SynAGE to O.S.

Publisher Copyright:
© 2021, The Author(s).


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