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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
EMBO Molecular Medicine, Volume 10, No. 1, Year 2018
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Description
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. © 2017 The Authors. Published under the terms of the CC BY 4.0 license
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC5760849/bin/EMMM-10-22-s001.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5760849/bin/EMMM-10-22-s002.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5760849/bin/EMMM-10-22-s003.pdf
Authors & Co-Authors
Simone, Roberto
United Kingdom, London
Ucl Queen Square Institute of Neurology
Preza, Elisavet
United Kingdom, London
Ucl Queen Square Institute of Neurology
Heslegrave, Amanda J.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Gilbert Jaramillo, Javier Andres
United Kingdom, London
Ucl Queen Square Institute of Neurology
Ecuador, Guayaquil
Escuela Superior Politecnica Del Litoral Ecuador
Houlden, Henry H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Polke, James M.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Ismail, Mohamed A.
United States, Atlanta
Georgia State University
Stephens, Chad E.
United States, Atlanta
Georgia State University
Farahat, Abdelbasset A.
United States, Atlanta
Georgia State University
Wilson, W. David
United States, Atlanta
Georgia State University
Boykin, David Withers
United States, Atlanta
Georgia State University
Zetterberg, Henrik H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Sweden, Gothenburg
Göteborgs Universitet
United Kingdom, London
University College London
Wray, Selina
United Kingdom, London
Ucl Queen Square Institute of Neurology
Parkinson, Gary Nigel
United Kingdom, London
Ucl School of Pharmacy
Neidle, Stephen
United Kingdom, London
Ucl School of Pharmacy
Patani, Rickie
United Kingdom, London
Ucl Queen Square Institute of Neurology
Statistics
Citations: 156
Authors: 16
Affiliations: 9
Identifiers
Doi:
10.15252/emmm.201707850
ISSN:
17574676
Research Areas
Environmental
Health System And Policy
Mental Health