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 language | English (US) |
|---|---|
| Pages (from-to) | 1664-1680.e4 |
| Journal | Cell Chemical Biology |
| Volume | 26 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 19 2019 |
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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
Cite this
}
Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System. / Du, Zhiqiang; Valtierra, Stephanie; Cardona, Luzivette Robles; Dunne, Sara Fernandez; Luan, Chi Hao; Li, Liming.
In: Cell Chemical Biology, Vol. 26, No. 12, 19.12.2019, p. 1664-1680.e4.Research output: Contribution to journal › Article
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
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
UR - http://www.scopus.com/inward/record.url?scp=85076358251&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076358251&partnerID=8YFLogxK
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 -