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

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Raguseo, Federica 
Wang, Yiran 
Li, Jessica 
Howe, Marija Petrić 
Balendra, Rubika 


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 the expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigated the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of the diseases. 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 over healthy motor neurons by staining with a G4-selective fluorescent probe, revealing fluorescent 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 and FTD.



Humans, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, RNA, G-Quadruplexes, C9orf72 Protein, DNA Repeat Expansion

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Nature Communications

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Nature Portfolio
Royal Society (UF160152)
Royal Society (RF\ERE\210029)
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