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EMBO Mol Med. 2018 Jan;10(1):22-31. doi: 10.15252/emmm.201707850.

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

Author information

1
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
2
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK.
3
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
4
MRC Centre for Neuromuscular Disease UCL Institute of Neurology, London, UK.
5
MRC Prion Unit at UCL Institute of Prion Diseases, London, UK.
6
'Rita Levi Montalcini' Department of Neuroscience, ALS Centre University of Turin, Turin, Italy.
7
Neurogenetics Unit UCL Institute of Neurology, London, UK.
8
Department of Chemistry, Georgia State University, Atlanta, GA, USA.
9
Clinical Neurochemistry Laboratory Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry The Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden.
10
UK Dementia Research Institute at UCL UCL Institute of Neurology, London, UK.
11
Max Planck Institute for Biology of Ageing, Cologne, Germany.
12
UCL School of Pharmacy, London, UK.
13
UCL School of Pharmacy, London, UK s.neidle@ucl.ac.uk rickie.patani@ucl.ac.uk p.fratta@ucl.ac.uk a.isaacs@ucl.ac.uk.
14
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK s.neidle@ucl.ac.uk rickie.patani@ucl.ac.uk p.fratta@ucl.ac.uk a.isaacs@ucl.ac.uk.
15
MRC Centre for Neuromuscular Disease UCL Institute of Neurology, London, UK s.neidle@ucl.ac.uk rickie.patani@ucl.ac.uk p.fratta@ucl.ac.uk a.isaacs@ucl.ac.uk.
16
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK s.neidle@ucl.ac.uk rickie.patani@ucl.ac.uk p.fratta@ucl.ac.uk a.isaacs@ucl.ac.uk.

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

PMID:
29113975
PMCID:
PMC5760849
DOI:
10.15252/emmm.201707850
[Indexed for MEDLINE]
Free PMC Article

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