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High‐Throughput Screen of Natural Product Extracts in A Yeast Model of Polyglutamine Proteotoxicity
Author(s) -
Walter Gladis M.,
Raveh Avi,
Mok SueAnn,
McQuade Thomas J.,
Arevang Carl J.,
Schultz Pamela J.,
Smith Matthew C.,
Asare Samuel,
Cruz Patricia G.,
Wisen Susanne,
Matainaho Teatulohi,
Sherman David H.,
Gestwicki Jason E.
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12259
Subject(s) - proteotoxicity , yeast , natural product , microbiology and biotechnology , protein aggregation , biochemistry , biology , chemistry
Proteins with expanded polyglutamine (poly Q ) 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 poly Q 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 Δ P ro Q 103‐expressing yeast cells in 384‐well plates ( Z ' ~ 0.7, CV ~ 8%). This screen identified actinomycin D as a strong inhibitor of poly Q 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 H sp104, H sp70 and H sp26 and enhanced binding of H sp70 to the poly Q in yeast. Actinomycin also suppressed aggregation of poly Q in mammalian cells, suggesting a conserved mechanism. These results establish natural products as a rich source of compounds with interesting mechanisms of action against poly Q disorders.