Using budding yeast to screen for anti-prion drugs.
Prions are misfolded proteins capable of propagating their altered conformation which are commonly considered as the causative agent of transmissible spongiform encephalopathies, a class of fatal neurodegenerative diseases. Currently, no treatment for prion-based diseases is available. Recently we have developed a rapid, yeast-based, two-step assay to screen for anti-prion drugs [1]. This new method allowed us to identify several compounds that are effective in vivo against budding yeast [PSI+] and [URE3] prions but also able to promote mammalian prion clearance in three different cell culture-based assays. Taken together, these results validate our method as an economic and efficient high-throughput screening approach to identify novel prion inhibitors or to carry on comprehensive structure-activity studies for already isolated anti-mammalian prion drugs. These results suggest furthermore that biochemical pathways controlling prion formation and/or maintenance are conserved from yeast to human and thus amenable to pharmacological and genetic analysis. Finally, it would be very interesting to test active drugs isolated using the yeast-based assay in models for other diseases (neurodegenerative or not) involving amyloid fibers like Huntington's, Parkinson's or Alzheimer's diseases.
Tribouillard
Déborah
D
CNRS UMR7150, Amyloids and Cell Division Cycle Laboratory, Station Biologique, Roscoff, Bretagne, France.
Bach
Stéphane
S
Gug
Fabienne
F
Desban
Nathalie
N
Beringue
Vincent
V
Andrieu
Thibault
T
Dormont
Dominique
D
Galons
Hervé
H
Laude
Hubert
H
Vilette
Didier
D
Blondel
Marc
M
D001681:Biological Assay / Q000379:methods*; D005979:Glutathione Peroxidase; D010454:Peptide Termination Factors; D011328:Prions / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D004718:Saccharomycetales / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae