MilliporeSigma
  • Home
  • Search Results
  • A Chemical Screen Identifies Compounds Limiting the Toxicity of C9ORF72 Dipeptide Repeats.

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

Cell chemical biology (2018-12-12)
Alba Corman, Bomi Jung, Maria Häggblad, Lars Bräutigam, Vanesa Lafarga, Louise Lidemalm, Daniela Hühn, Jordi Carreras-Puigvert, Oscar Fernandez-Capetillo
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bromosporine, ≥98% (HPLC)
Sigma-Aldrich
Cycloheximide, from microbial, ≥94% (TLC)
Sigma-Aldrich
Actinomycin D, from Streptomyces sp., ~98% (HPLC)
Sigma-Aldrich
Protease from Streptomyces griseus, Type XIV, ≥3.5 units/mg solid, powder
Sigma-Aldrich
Anti-UTP3 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-NOL7 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Sodium phenylbutyrate, ≥98% (HPLC)
Sigma-Aldrich
(+/-)-JQ1, ≥98% (HPLC)
Sigma-Aldrich
Anti-PES1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody
Sigma-Aldrich
Anti-DDX10 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-UBTF antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
bisBenzimide H 33342 trihydrochloride, for fluorescence, ≥97.0% (HPLC)
Sigma-Aldrich
PFI-1, ≥98% (HPLC)
Sigma-Aldrich
Anti-NOC2L antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-MAK16 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution