3 years ago

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

G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
Rickie Patani, Elisavet Preza, Adrian M Isaacs, Chad E Stephens, Mica Clarke, Thomas G Moens, James M Polke, Amanda Heslegrave, Selina Wray, Henrik Zetterberg, Tam Vo, Andrew J Nicoll, W David Wilson, Gary Parkinson, Jamie S Mitchell, David W Boykin, Nathan S Woodling, Mohamed A Ismail, Stephen Neidle, Roberto Simone, Javier Gilbert-Jaramillo, Abdelbasset A Farahat, Emma L Clayton, Teresa Niccoli, Katherine M Wilson, Pietro Fratta, Rubika Balendra, Adriano Chio, Marie-Therese Konrad, Samir Abdelkarim, Henry Houlden, Andrea Calvo, Linda Partridge
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. Small molecules targeting G-quadruplex GGGGCC repeat RNA are effective at ameliorating disease phenotypes in C9orf72 patient neurons, and in vivo phenotypes in C9orf72 flies. Therefore, targeting expanded GGGGCC RNA could be an effective therapeutic strategy for C9orf72 ALS and FTD.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/emmm.201707850

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