Open AccessG‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo
Author(s) -
Simone Roberto,
Balendra Rubika,
Moens Thomas G,
Preza Elisavet,
Wilson Katherine M,
Heslegrave Amanda,
Woodling Nathan S,
Niccoli Teresa,
GilbertJaramillo Javier,
Abdelkarim Samir,
Clayton Emma L,
Clarke Mica,
Konrad MarieTherese,
Nicoll Andrew J,
Mitchell Jamie S,
Calvo Andrea,
Chio Adriano,
Houlden Henry,
Polke James M,
Ismail Mohamed A,
Stephens Chad E,
Vo Tam,
Farahat Abdelbasset A,
Wilson W David,
Boykin David W,
Zetterberg Henrik,
Partridge Linda,
Wray Selina,
Parkinson Gary,
Neidle Stephen,
Patani Rickie,
Fratta Pietro,
Isaacs Adrian M
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201707850
Subject(s) - c9orf72 , frontotemporal dementia , rna , trinucleotide repeat expansion , amyotrophic lateral sclerosis , in vivo , small molecule , chemistry , biology , microbiology and biotechnology , cancer research , medicine , biochemistry , pathology , genetics , disease , dementia , gene , allele
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.