TY - JOUR
T1 - Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System
AU - Du, Zhiqiang
AU - Valtierra, Stephanie
AU - Cardona, Luzivette Robles
AU - Dunne, Sara Fernandez
AU - Luan, Chi Hao
AU - Li, Liming
N1 - Funding Information:
The authors thank Gabriela Caraveo Piso (Northwestern University) for the yeast expression strains of neurodegeneration-linked pathogenic proteins; Randall Halfmann (Stowers Institute) for the [ MOT3 + ] donor strain and other experimental materials and Reed Wickner (Laboratory of Biochemistry and Genetics, NIH) for the [URE3] strain; and Dustin Goncharoff for critical comments of this study and for manuscript editing. This work was supported by grants from the National Institutes of Health , United States ( R01GM110045 ), National Science Foundation , United States ( MCB 1122135 ) to L.L., and National Institutes of Health, United States ( R01GM126318 ) to Z.D.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/12/19
Y1 - 2019/12/19
N2 - 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.
AB - 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.
KW - Saccharomyces cerevisiae
KW - amyloids
KW - anti-prion compounds
KW - high-throughput screening
KW - neurodegenerative diseases
KW - prion
KW - protein aggregation
KW - swi1
KW - yeast
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U2 - 10.1016/j.chembiol.2019.10.004
DO - 10.1016/j.chembiol.2019.10.004
M3 - Article
C2 - 31668517
AN - SCOPUS:85076358251
VL - 26
SP - 1664-1680.e4
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 12
ER -
