Imperial College London
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DrLorenzoDi Michele

Faculty of Natural Sciences, Department of Chemistry

Honorary Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3262l.di-michele Website

 
 
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Location

 

Molecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Raguseo:2023:10.1038/s41467-023-43872-1,
author = {Raguseo, F and Wang, Y and Li, J and Petri, Howe M and Balendra, R and Huyghebaert, A 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 Di, Michele L and Di, Antonio M},
doi = {10.1038/s41467-023-43872-1},
journal = {Nature Communications},
title = {The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes},
url = {http://dx.doi.org/10.1038/s41467-023-43872-1},
volume = {14},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Raguseo,F
AU  - Wang,Y
AU  - Li,J
AU  - Petri,Howe M
AU  - Balendra,R
AU  - Huyghebaert,A
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  - Di,Michele L
AU  - Di,Antonio M
DO  - 10.1038/s41467-023-43872-1
PY  - 2023///
SN  - 2041-1723
TI  - The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/s41467-023-43872-1
UR  - http://hdl.handle.net/10044/1/108236
VL  - 14
ER  -
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