Anti-Prion Systems in Saccharomyces cerevisiae

Area of Science:

• Molecular Biology
• Protein Chemistry
• Genetics

Background:

• Yeast prions, such as [PSI+] (Sup35p) and [URE3] (Ure2p), are infectious proteins that mimic mammalian prion diseases.
• These prions are associated with essential cellular functions, including translation termination and nitrogen metabolism.

Purpose of the Study:

• To investigate the history and mechanisms of anti-prion defense systems in Saccharomyces cerevisiae.
• To understand how these systems prevent prion infection, generation, propagation, and toxicity.
• To explore the potential of yeast anti-prion systems as models for human amyloid diseases.

Main Methods:

• Historical tracing of yeast prion research.
• Description and analysis of multiple anti-prion systems in yeast.
• Quantification of the inhibitory effects of individual and combined anti-prion systems on prion appearance.
• Screening for human anti-prion proteins using yeast prion models.

Main Results:

• S. cerevisiae employs an array of anti-prion systems that collectively inhibit prion formation and propagation.
• Ribosome-associated chaperones, Hsp104 disaggregase, and Upf proteins synergistically reduce [PSI+] appearance by approximately 5000-fold.
• Most [PSI+] variants exhibit sensitivity to these anti-prion systems.
• Five human Bag protein family members demonstrate anti-prion activity in yeast models.

Conclusions:

• Yeast anti-prion systems provide robust protection against prion propagation and toxicity.
• The identified human anti-prion proteins suggest potential therapeutic targets for human amyloidosis.
• Manipulation of human anti-prion systems may offer a strategy for preventing or treating prion-based human diseases.