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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 22-31 |
| Number of pages | 10 |
| Journal | EMBO Molecular Medicine |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2018 |
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Keywords
- C9orf72
- G-quadruplex
- amyotrophic lateral sclerosis
- frontotemporal dementia
ASJC Scopus subject areas
- Molecular Medicine
Cite this
G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. / Simone, Roberto; Balendra, Rubika; Moens, Thomas G.; Preza, Elisavet; Wilson, Katherine M.; Heslegrave, Amanda; Woodling, Nathan S.; Niccoli, Teresa; Gilbert-Jaramillo, Javier; Abdelkarim, Samir; Clayton, Emma L.; Clarke, Mica; Konrad, Marie Therese; 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.
In: EMBO Molecular Medicine, Vol. 10, No. 1, 01.2018, p. 22-31.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
AU - Simone, Roberto
AU - Balendra, Rubika
AU - Moens, Thomas G.
AU - Preza, Elisavet
AU - Wilson, Katherine M.
AU - Heslegrave, Amanda
AU - Woodling, Nathan S.
AU - Niccoli, Teresa
AU - Gilbert-Jaramillo, Javier
AU - Abdelkarim, Samir
AU - Clayton, Emma L.
AU - Clarke, Mica
AU - Konrad, Marie Therese
AU - Nicoll, Andrew J.
AU - Mitchell, Jamie S.
AU - Calvo, Andrea
AU - Chio, Adriano
AU - Houlden, Henry
AU - Polke, James M.
AU - Ismail, Mohamed A.
AU - Stephens, Chad E.
AU - Vo, Tam
AU - Farahat, Abdelbasset A.
AU - Wilson, W. David
AU - Boykin, David W.
AU - Zetterberg, Henrik
AU - Partridge, Linda
AU - Wray, Selina
AU - Parkinson, Gary
AU - Neidle, Stephen
AU - Patani, Rickie
AU - Fratta, Pietro
AU - Isaacs, Adrian M.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - C9orf72
KW - G-quadruplex
KW - amyotrophic lateral sclerosis
KW - frontotemporal dementia
UR - http://www.scopus.com/inward/record.url?scp=85040286038&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040286038&partnerID=8YFLogxK
U2 - 10.15252/emmm.201707850
DO - 10.15252/emmm.201707850
M3 - Article
C2 - 29113975
AN - SCOPUS:85040286038
VL - 10
SP - 22
EP - 31
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 1
ER -