G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo

Simone, R. et al. (2018) G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Molecular Medicine, 10(1), pp. 22-31. (doi: 10.15252/emmm.201707850) (PMID:29113975) (PMCID:PMC5760849)

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.

• Item Type: Articles
• Additional Information: 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’sResearch 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’s NIHR Biomedical Research Centres funding scheme.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Woodling, Dr Nathan
• Authors: Simone, R., Balendra, R., Moens, T. G., Preza, E., Wilson, K. M., Heslegrave, A., Woodling, N. S., Niccoli, T., Gilbert-Jaramillo, J., Abdelkarim, S., Clayton, E. L., Clarke, M., Konrad, M.-T., Nicoll, A. J., Mitchell, J. S., Calvo, A., Chio, A., Houlden, H., Polke, J. M., Ismail, M. A., Stephens, C. E., Vo, T., Farahat, A. A., Wilson, W. D., Boykin, D. W., Zetterberg, H., Partridge, L., Wray, S., Parkinson, G., Neidle, S., Patani, R., Fratta, P., and Isaacs, A. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: EMBO Molecular Medicine
• Publisher: Wiley Open Access for EMBO Press
• ISSN: 1757-4676
• ISSN (Online): 1757-4684
• Copyright Holders: Copyright: © 2017 The Authors
• First Published: First published in EMBO Molecular Medicine 10(1): 22-31
• Publisher Policy: Reproduced under a Creative Commons licence

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