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

doi:10.1016/j.chembiol.2019.10.004

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 journal › Article › peer-review

9 Scopus citations

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-PrP^Sc 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 language	English (US)
Pages (from-to)	1664-1680.e4
Journal	Cell Chemical Biology
Volume	26
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2019.10.004
State	Published - Dec 19 2019

Funding

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.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2019.10.004

Cite this

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title = "Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System",

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.",

keywords = "Saccharomyces cerevisiae, amyloids, anti-prion compounds, high-throughput screening, neurodegenerative diseases, prion, protein aggregation, swi1, yeast",

author = "Zhiqiang Du and Stephanie Valtierra and Cardona, {Luzivette Robles} and Dunne, {Sara Fernandez} and Luan, {Chi Hao} and Liming Li",

note = "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: {\textcopyright} 2019 Elsevier Ltd",

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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

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KW - protein aggregation

KW - swi1

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SN - 2451-9456

VL - 26

SP - 1664-1680.e4

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 12

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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