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G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
Simone R, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Woodling NS, Niccoli T et al.. EMBO molecular medicine, 2018-01-01
Topic: Brain proteins, microglia and lab models
Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo , in GGGGCC repeat-expressing Drosophila Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential.
Key findings
- We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins.
- Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo , in GGGGCC repeat-expressing Drosophila Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential.
Why it matters
In cells from patients with C9orf72 frontotemporal dementia/ALS and in flies, small molecules that stabilize a specific RNA structure reduced two key pathologies and improved survival. These are early laboratory and animal findings for a different condition and have not been shown to treat or prevent Alzheimer's disease in people.
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Study details
- Evidence strengthLow
How this study scored 49/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (EMBO molecular medicine) |
| Journal's citation record | 2 / 4 | EMBO Molecular Medicine: journal h-index 186 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2018 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 217 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 21.7 citations a year over 10 year(s) since 2018 |
| Impact for its field and year | 4 / 6 | Cited 13.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 47 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Adrian M. Isaacs: h-index 51 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 29113975) |
| Free to read | 2 / 2 | Free to read |
| Total | 49 / 100 | — |
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Read the original
- DOI: 10.15252/emmm.201707850
- PubMed: 29113975
- Original source →
- Free full text: EMBO Molecular Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Simone, R., Balendra, R., Moens, T. G., Preza, E., Wilson, K. M., Heslegrave, A., et al. (2018). G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO molecular medicine. https://doi.org/10.15252/emmm.201707850
Vancouver
Simone R, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, et al. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO molecular medicine. 2018. doi:10.15252/emmm.201707850. PMID: 29113975.
BibTeX
@article{simone2018-29113975,
author = {Simone, R. and Balendra, R. and Moens, T. G. and Preza, E. and Wilson, K. M. and Heslegrave, A. and Woodling, N. S. and Niccoli, T. and others},
title = {{G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo}},
journal = {EMBO molecular medicine},
year = {2018},
doi = {10.15252/emmm.201707850},
pmid = {29113975},
url = {https://doi.org/10.15252/emmm.201707850}
}
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