Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System

Zhiqiang Du*, Stephanie Valtierra, Luzivette Robles Cardona, Sara Fernandez Dunne, Chi Hao Luan, Liming Li

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI+]. We show that some identified anti-[SWI+] compounds can destabilize other non-[SWI+] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrPSc compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.

Original languageEnglish (US)
Pages (from-to)1664-1680.e4
JournalCell Chemical Biology
Volume26
Issue number12
DOIs
StatePublished - Dec 19 2019

Keywords

  • Saccharomyces cerevisiae
  • amyloids
  • anti-prion compounds
  • high-throughput screening
  • neurodegenerative diseases
  • prion
  • protein aggregation
  • swi1
  • yeast

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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