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High-throughput Screening for Protein-based Inheritance in S. cerevisiae
Published on: August 8, 2017
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Functional genomics screen identifies proteostasis targets that modulate prion protein (PrP) stability.
Jennifer Abrams1,2, Taylor Arhar1,2, Sue Ann Mok1,2
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Cell Stress & Chaperones
|February 6, 2021
Summary
Researchers screened protein homeostasis factors to find regulators of prion protein (PrPC) stability. They identified Hsp70 chaperones as key targets, showing that inhibiting Hsp70 reduces PrPC and Creutzfeldt-Jacob disease (CJD) progression.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Prion protein (PrP) misfolding into PrPSc causes fatal neurodegenerative diseases like CJD.
- Reducing PrPC levels is a therapeutic strategy against prion diseases.
- Protein homeostasis (proteostasis) factors regulate protein stability.
Purpose of the Study:
- To identify proteostasis factors that regulate PrPC stability.
- To explore therapeutic targets for CJD by understanding PrPC regulation.
Main Methods:
- Assembled a library of shRNA targeting 133 proteostasis factors.
- Screened the library in HEK293 Hu129M cells to find PrPC regulators.
- Validated findings using a chemical Hsp70 inhibitor in N2a cells.
Main Results:
- Identified Hsp70 family members and co-chaperones as key regulators of PrPC stability.
- Demonstrated that Hsp70 inhibition reduces PrPC levels.
- Showed that Hsp70 inhibition limits PrPSc conversion in cells.
Conclusions:
- The Hsp70 system is a critical regulator of PrPC and a potential therapeutic target for CJD.
- The Proteostasis shRNA Library is a valuable tool for identifying protein regulators.
