TY  - JOUR
AU  - Czuppa, Mareike
AU  - Dhingra, Ashutosh
AU  - Zhou, Qihui
AU  - Schludi, Carina
AU  - Koenig, Laura
AU  - Scharf, Elisabeth
AU  - Farny, Daniel
AU  - Dalmia, Anupriya
AU  - Täger, Joachim
AU  - Castillo Lizardo, Melissa Gissel
AU  - Katona, Eszter
AU  - Mori, Kohji
AU  - Aumer, Tina
AU  - Schelter, Florian
AU  - Müller, Markus
AU  - Carell, Thomas
AU  - Kalliokoski, Tuomo
AU  - Messinger, Josef
AU  - Rizzu, Patrizia
AU  - Heutink, Peter
AU  - Edbauer, Dieter
TI  - Drug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD
JO  - Cell reports
VL  - 39
IS  - 10
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - DZNE-2022-01175
SP  - 110913
PY  - 2022
N1  - (CC BY-NC-ND)
AB  - An intronic (G4C2)n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with minimal effects on global gene expression, suggesting that they specifically act on repeat transcription. Importantly, decitabine treatment reduces (G4C2)n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders.
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Animals
KW  - C9orf72 Protein: genetics
KW  - C9orf72 Protein: metabolism
KW  - DNA Repeat Expansion
KW  - Decitabine: metabolism
KW  - Dipeptides: metabolism
KW  - Frontotemporal Dementia: genetics
KW  - Humans
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Mice
KW  - Neurons: metabolism
KW  - Nucleosides: metabolism
KW  - RNA, Antisense: metabolism
LB  - PUB:(DE-HGF)16
C6  - pmid:35675776
DO  - DOI:10.1016/j.celrep.2022.110913
UR  - https://pub.dzne.de/record/164645
ER  -