@article{Raguseo:2023:10.1101/2023.01.31.526399,
author = {Raguseo, F and Huyghebaert, A and Li, J and Balendra, R and Howe, MP and Wang, Y and Vadukul, DM and Tanase, DA and Maher, TE and Malouf, L and Rubio-Sánchez, R and Aprile, FA and Elani, Y and Patani, R and Michele, LD and Antonio, MD},
doi = {10.1101/2023.01.31.526399},
title = {The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes},
url = {http://dx.doi.org/10.1101/2023.01.31.526399},
year = {2023}
}

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TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>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)<jats:italic><jats:sub>n</jats:sub></jats:italic>in<jats:italic>C9orf72</jats:italic>. 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 observed significant aggregation of the hexanucleotide sequence (GGGGCC)<jats:italic><jats:sub>n</jats:sub></jats:italic>, which we associated to the formation of multimolecular G-quadruplexes (mG4s), using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions led to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validated the biological relevance of our findings by demonstrating the ability of a G4-selective fluorescent probe to penetrate<jats:italic>C9orf72</jats:italic>mutant human motor neurons derived from ALS patients, which revealed clear 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<jats:italic>C9orf72</jats:italic>mutation related ALS and FTD.</jats:p><jats:p><jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="526399v3_ufig1" position="float" orientation="portrait" /></jats:fig></jats:p>
AU  - Raguseo,F
AU  - Huyghebaert,A
AU  - Li,J
AU  - Balendra,R
AU  - Howe,MP
AU  - Wang,Y
AU  - Vadukul,DM
AU  - Tanase,DA
AU  - Maher,TE
AU  - Malouf,L
AU  - Rubio-Sánchez,R
AU  - Aprile,FA
AU  - Elani,Y
AU  - Patani,R
AU  - Michele,LD
AU  - Antonio,MD
DO  - 10.1101/2023.01.31.526399
PY  - 2023///
TI  - The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes
UR  - http://dx.doi.org/10.1101/2023.01.31.526399
ER  - 

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