EMBO Molecular Medicine (Jan 2018)
G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
- Roberto Simone,
- Rubika Balendra,
- Thomas G Moens,
- Elisavet Preza,
- Katherine M Wilson,
- Amanda Heslegrave,
- Nathan S Woodling,
- Teresa Niccoli,
- Javier Gilbert‐Jaramillo,
- Samir Abdelkarim,
- Emma L Clayton,
- Mica Clarke,
- Marie‐Therese Konrad,
- Andrew J Nicoll,
- Jamie S Mitchell,
- Andrea Calvo,
- Adriano Chio,
- Henry Houlden,
- James M Polke,
- Mohamed A Ismail,
- Chad E Stephens,
- Tam Vo,
- Abdelbasset A Farahat,
- W David Wilson,
- David W Boykin,
- Henrik Zetterberg,
- Linda Partridge,
- Selina Wray,
- Gary Parkinson,
- Stephen Neidle,
- Rickie Patani,
- Pietro Fratta,
- Adrian M Isaacs
Affiliations
- Roberto Simone
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Rubika Balendra
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Thomas G Moens
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Elisavet Preza
- Department of Molecular Neuroscience UCL Institute of Neurology London UK
- Katherine M Wilson
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Amanda Heslegrave
- Department of Molecular Neuroscience UCL Institute of Neurology London UK
- Nathan S Woodling
- Department of Genetics, Evolution and Environment Institute of Healthy Ageing University College London London UK
- Teresa Niccoli
- Department of Genetics, Evolution and Environment Institute of Healthy Ageing University College London London UK
- Javier Gilbert‐Jaramillo
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Samir Abdelkarim
- MRC Centre for Neuromuscular Disease UCL Institute of Neurology London UK
- Emma L Clayton
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Mica Clarke
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Marie‐Therese Konrad
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Andrew J Nicoll
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Jamie S Mitchell
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- Andrea Calvo
- ‘Rita Levi Montalcini’ Department of Neuroscience, ALS Centre University of Turin Turin Italy
- Adriano Chio
- ‘Rita Levi Montalcini’ Department of Neuroscience, ALS Centre University of Turin Turin Italy
- Henry Houlden
- Department of Molecular Neuroscience UCL Institute of Neurology London UK
- James M Polke
- Neurogenetics Unit UCL Institute of Neurology London UK
- Mohamed A Ismail
- Department of Chemistry Georgia State University Atlanta GA USA
- Chad E Stephens
- Department of Chemistry Georgia State University Atlanta GA USA
- Tam Vo
- Department of Chemistry Georgia State University Atlanta GA USA
- Abdelbasset A Farahat
- Department of Chemistry Georgia State University Atlanta GA USA
- W David Wilson
- Department of Chemistry Georgia State University Atlanta GA USA
- David W Boykin
- Department of Chemistry Georgia State University Atlanta GA USA
- Henrik Zetterberg
- Department of Molecular Neuroscience UCL Institute of Neurology London UK
- Linda Partridge
- Department of Genetics, Evolution and Environment Institute of Healthy Ageing University College London London UK
- Selina Wray
- Department of Molecular Neuroscience UCL Institute of Neurology London UK
- Gary Parkinson
- UCL School of Pharmacy London UK
- Stephen Neidle
- UCL School of Pharmacy London UK
- Rickie Patani
- Department of Molecular Neuroscience UCL Institute of Neurology London UK
- Pietro Fratta
- MRC Centre for Neuromuscular Disease UCL Institute of Neurology London UK
- Adrian M Isaacs
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- DOI
- https://doi.org/10.15252/emmm.201707850
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 22 – 31
Abstract
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.
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