A Chemical Screen Identifies Compounds Limiting the Toxicity of C9ORF72 Dipeptide Repeats

Cell Chem Biol. 2019 Feb 21;26(2):235-243.e5. doi: 10.1016/j.chembiol.2018.10.020. Epub 2018 Dec 6.


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.

Keywords: ALS; BET Bromodomain; C9ORF72; arginine-rich peptides; chemical screen; dipeptide repeat proteins; nucleolar stress; sodium phenylbutyrate; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Apoptosis / drug effects*
  • C9orf72 Protein / chemistry*
  • 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
  • Peptides / toxicity*
  • Proteins / antagonists & inhibitors
  • Proteins / metabolism
  • Zebrafish / growth & development


  • C9orf72 Protein
  • Chromosomal Proteins, Non-Histone
  • Histone Deacetylase Inhibitors
  • Peptides
  • Proteins
  • bromodomain and extra-terminal domain protein, human
  • fibrillarin
  • Dactinomycin

Supplementary concepts

  • Frontotemporal Dementia With Motor Neuron Disease