Journal Article

DZNE-2022-01175

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Drug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD

Czuppa, M. (First author)DZNE* ; Dhingra, A.DZNE* ; Zhou, Q.DZNE* ; Schludi, C.DZNE* ; Koenig, L.DZNE* ; Scharf, E.DZNE* ; Farny, D.DZNE* ; Dalmia, A.DZNE* ; Täger, J.DZNE* ; Castillo Lizardo, M. G.DZNE* ; Katona, E.DZNE* ; Mori, K. ; Aumer, T. ; Schelter, F. ; Müller, M. ; Carell, T. ; Kalliokoski, T. ; Messinger, J. ; Rizzu, P.DZNE* ; Heutink, P.DZNE* ; Edbauer, D. (Last author)DZNE*

2022
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2022.110913

Abstract: 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.

Keyword(s): Amyotrophic Lateral Sclerosis: drug therapy (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Animals (MeSH) ; C9orf72 Protein: genetics (MeSH) ; C9orf72 Protein: metabolism (MeSH) ; DNA Repeat Expansion (MeSH) ; Decitabine: metabolism (MeSH) ; Dipeptides: metabolism (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Mice (MeSH) ; Neurons: metabolism (MeSH) ; Nucleosides: metabolism (MeSH) ; RNA, Antisense: metabolism (MeSH)

Note: (CC BY-NC-ND)

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)
2. Genome Biology of Neurodegenerative Diseases (AG Heutink 1)
3. München common (München common)
4. Applied Genomics of Neurodegenerative Diseases (AG Rizzu)
5. Adaptive Immunity in Neurodegeneration (AG Zhou)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2022

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