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

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, Francesco A. Aprile, Yuval Elani, Rickie Patani (), Lorenzo Di Michele () and Marco Di Antonio ()
Additional contact information
Federica Raguseo: Molecular Sciences Research Hub
Yiran Wang: The Francis Crick Institute
Jessica Li: The Francis Crick Institute
Marija Petrić Howe: The Francis Crick Institute
Rubika Balendra: The Francis Crick Institute
Anouk Huyghebaert: Molecular Sciences Research Hub
Devkee M. Vadukul: Molecular Sciences Research Hub
Diana A. Tanase: Molecular Sciences Research Hub
Thomas E. Maher: Molecular Sciences Research Hub
Layla Malouf: Molecular Sciences Research Hub
Roger Rubio-Sánchez: University of Cambridge, Department of Chemical Engineering and Biotechnology
Francesco A. Aprile: Molecular Sciences Research Hub
Yuval Elani: Imperial College London, Department of Chemical Engineering
Rickie Patani: The Francis Crick Institute
Lorenzo Di Michele: Molecular Sciences Research Hub
Marco Di Antonio: Molecular Sciences Research Hub

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43872-1

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