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The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Author

Listed:
  • Federica Raguseo

    (Molecular Sciences Research Hub
    University of Cambridge, Department of Chemical Engineering and Biotechnology
    Molecular Sciences Research Hub)

  • Yiran Wang

    (The Francis Crick Institute
    University College London)

  • Jessica Li

    (The Francis Crick Institute
    University College London)

  • Marija Petrić Howe

    (The Francis Crick Institute
    University College London)

  • Rubika Balendra

    (The Francis Crick Institute
    University College London)

  • Anouk Huyghebaert

    (Molecular Sciences Research Hub
    Molecular Sciences Research Hub)

  • Devkee M. Vadukul

    (Molecular Sciences Research Hub)

  • Diana A. Tanase

    (Molecular Sciences Research Hub
    University of Cambridge, Department of Chemical Engineering and Biotechnology)

  • Thomas E. Maher

    (Molecular Sciences Research Hub
    Molecular Sciences Research Hub)

  • Layla Malouf

    (Molecular Sciences Research Hub
    University of Cambridge, Department of Chemical Engineering and Biotechnology)

  • Roger Rubio-Sánchez

    (University of Cambridge, Department of Chemical Engineering and Biotechnology)

  • Francesco A. Aprile

    (Molecular Sciences Research Hub
    Molecular Sciences Research Hub)

  • Yuval Elani

    (Imperial College London, Department of Chemical Engineering)

  • Rickie Patani

    (The Francis Crick Institute
    University College London)

  • Lorenzo Di Michele

    (Molecular Sciences Research Hub
    University of Cambridge, Department of Chemical Engineering and Biotechnology)

  • Marco Di Antonio

    (Molecular Sciences Research Hub
    Molecular Sciences Research Hub
    The Francis Crick Institute)

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.

Suggested Citation

  • Federica Raguseo & Yiran Wang & Jessica Li & Marija Petrić Howe & Rubika Balendra & Anouk Huyghebaert & Devkee M. Vadukul & Diana A. Tanase & Thomas E. Maher & Layla Malouf & Roger Rubio-Sánchez & Fra, 2023. "The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43872-1
    DOI: 10.1038/s41467-023-43872-1
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    References listed on IDEAS

    as
    1. Marina Garcia-Jove Navarro & Shunnichi Kashida & Racha Chouaib & Sylvie Souquere & Gérard Pierron & Dominique Weil & Zoher Gueroui, 2019. "RNA is a critical element for the sizing and the composition of phase-separated RNA–protein condensates," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. J. Paul Taylor & Robert H. Brown & Don W. Cleveland, 2016. "Decoding ALS: from genes to mechanism," Nature, Nature, vol. 539(7628), pages 197-206, November.
    3. Ankur Jain & Ronald D. Vale, 2017. "RNA phase transitions in repeat expansion disorders," Nature, Nature, vol. 546(7657), pages 243-247, June.
    Full references (including those not matched with items on IDEAS)

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