@article{79e0fac9a80d440899096cb390e40a19,
title = "G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo",
abstract = "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.",
keywords = "C9orf72, G-quadruplex, amyotrophic lateral sclerosis, frontotemporal dementia",
author = "Roberto Simone and Rubika Balendra and Moens, {Thomas G.} and Elisavet Preza and Wilson, {Katherine M.} and Amanda Heslegrave and Woodling, {Nathan S.} and Teresa Niccoli and Javier Gilbert-Jaramillo and Samir Abdelkarim and Clayton, {Emma L.} and Mica Clarke and Konrad, {Marie Therese} and Nicoll, {Andrew J.} and Mitchell, {Jamie S.} and Andrea Calvo and Adriano Chio and Henry Houlden and Polke, {James M.} and Ismail, {Mohamed A.} and Stephens, {Chad E.} and Tam Vo and Farahat, {Abdelbasset A.} and Wilson, {W. David} and Boykin, {David W.} and Henrik Zetterberg and Linda Partridge and Selina Wray and Gary Parkinson and Stephen Neidle and Rickie Patani and Pietro Fratta and Isaacs, {Adrian M.}",
note = "Funding Information: We thank Professor Chris Shaw for providing C9orf72 iPSC line 3 and Lucy Minkley for technical assistance. This work was funded by the Thierry Latran Foundation (AMI, PF, GP), ERC (AMI, H2020-ERC-2014-CoG-648716), MRC (PF, MR/M008606/1), Brain Research Trust (TGM), Alzheimer{\textquoteright}s Research UK (SW, AMI, ARUK-PPG2012B-13), Leonard Wolfson Foundation (AJH), NIH (GM111749 to W. D. W. and D. W. B), and Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe), which is funded through a collaboration between NCATS and National Institute of Neurological Disorders and Stroke. RB is a Leonard Wolfson Clinical Research Training Fellow and funded by a Wellcome Trust Research Training Fellowship (107196/Z/14/Z). HZ is a Wallenberg Academy Fellow. SW and EP are supported by the NIHR Queen Square Dementia Biomedical Research Unit. RP is a Wellcome Trust Intermediate Clinical Fellow (101149/Z/13/A). Some of this work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health{\textquoteright}s NIHR Biomedical Research Centres funding scheme.",
year = "2018",
month = jan,
doi = "10.15252/emmm.201707850",
language = "English (US)",
volume = "10",
pages = "22--31",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "1",
}