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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
High-throughput screen of natural product extracts in a yeast model of polyglutamine proteotoxicity
Chemical Biology and Drug Design, Volume 83, No. 4, Year 2014
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Description
Proteins with expanded polyglutamine (polyQ) segments cause a number of fatal neurodegenerative disorders, including Huntington's disease (HD). Previous high-throughput screens in cellular and biochemical models of HD have revealed compounds that mitigate polyQ aggregation and proteotoxicity, providing insight into the mechanisms of disease and leads for potential therapeutics. However, the structural diversity of natural products has not yet been fully mobilized toward these goals. Here, we have screened a collection of ~11 000 natural product extracts for the ability to recover the slow growth of ΔProQ103-expressing yeast cells in 384-well plates (Z' ~ 0.7, CV ~ 8%). This screen identified actinomycin D as a strong inhibitor of polyQ aggregation and proteotoxicity at nanomolar concentrations (~50-500 ng/mL). We found that a low dose of actinomycin D increased the levels of the heat-shock proteins Hsp104, Hsp70 and Hsp26 and enhanced binding of Hsp70 to the polyQ in yeast. Actinomycin also suppressed aggregation of polyQ in mammalian cells, suggesting a conserved mechanism. These results establish natural products as a rich source of compounds with interesting mechanisms of action against polyQ disorders. A 'live-dead' assay for polyQ toxicity was developed and miniaturized for 384-well format. Activators of a stress response were identified as anti-polyQ compounds by screening a pre-fractionated natural product collection. © 2014 John Wiley & Sons A/S.
Authors & Co-Authors
Walter, Gladis M.
Unknown Affiliation
Raveh, Avi
Unknown Affiliation
Mok, Sue Ann
Unknown Affiliation
McQuade, Thomas J.
Unknown Affiliation
Arevang, Carl J.
Unknown Affiliation
Schultz, Pamela J.
Unknown Affiliation
Smith, Matthew C.
Unknown Affiliation
Asare, Samuel
Unknown Affiliation
Cruz, Patricia G.
Unknown Affiliation
Wisen, Susanne
Unknown Affiliation
Matainaho, Teatulohi
Unknown Affiliation
Sherman, David H.
Unknown Affiliation
Gestwicki, Jason E.
Unknown Affiliation
Statistics
Citations: 13
Authors: 13
Affiliations: 5
Identifiers
Doi:
10.1111/cbdd.12259
ISSN:
17470277
e-ISSN:
17470285