1. A Chemical Screen Identifies Compounds Limiting the Toxicity of C9ORF72 Dipeptide Repeats.
- Author
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Corman A, Jung B, Häggblad M, Bräutigam L, Lafarga V, Lidemalm L, Hühn D, Carreras-Puigvert J, and Fernandez-Capetillo O
- Subjects
- Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Animals, C9orf72 Protein genetics, C9orf72 Protein metabolism, Cell Line, Tumor, Cell Nucleolus drug effects, Cell Nucleolus metabolism, Chromosomal Proteins, Non-Histone metabolism, DNA Repeat Expansion, Dactinomycin toxicity, Embryo, Nonmammalian drug effects, Embryo, Nonmammalian physiology, Frontotemporal Dementia metabolism, Frontotemporal Dementia pathology, Histone Deacetylase Inhibitors pharmacology, Humans, Peptides chemical synthesis, Proteins antagonists & inhibitors, Proteins metabolism, Zebrafish growth & development, Apoptosis drug effects, C9orf72 Protein chemistry, Peptides toxicity
- Abstract
The expansion of GGGGCC repeats within the first intron of C9ORF72 constitutes the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Through repeat-associated non-ATG translation, these expansions are translated into dipeptide repeats (DPRs), some of which accumulate at nucleoli and lead to cell death. We here performed a chemical screen to identify compounds reducing the toxicity of ALS-related poly(PR) peptides. Our screening identified sodium phenylbutyrate, currently in clinical trials, and BET Bromodomain inhibitors as modifiers of poly(PR) toxicity in cell lines and developing zebrafish embryos. Mechanistically, we show that BET Bromodomain inhibitors rescue the nucleolar stress induced by poly(PR) or actinomycin D, alleviating the effects of the DPR in nucleolus-related functions such as mRNA splicing or translation. Our work suggests that BET Bromodomain inhibitors might have beneficial effects in diseases linked to nucleolar stress such as ALS/FTD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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