Byline: Takao. Ishikawa
The baker's yeast Saccharomyces (S.) cerevisiae is a single-celled eukaryotic model organism widely used in research on life sciences. Being a unicellular organism, S. cerevisiae has some evident limitations in application to neuroscience. However, yeast prions are extensively studied and they are known to share some hallmarks with mammalian prion protein or other amyloidogenic proteins found in the pathogenesis of Alzheimer's, Parkinson's, or Huntington's diseases. Therefore, the yeast S. cerevisiae has been widely used for basic research on aggregation properties of proteins in cellulo and on their propagation. Recently, a yeast-based study revealed that some regions of mammalian prion protein and amyloid [sz][sub]1-42 are capable of induction and propagation of yeast prions. It is one of the examples showing that evolutionarily distant organisms share common mechanisms underlying the structural conversion of prion proteins making yeast cells a useful system for studying mammalian prion protein. S. cerevisiae has also been used to design novel screening systems for anti-prion compounds from chemical libraries. Yeast-based assays are cheap in maintenance and safe for the researcher, making them a very good choice to perform preliminary screening before further characterization in systems engaging mammalian cells infected with prions. In this review, not only classical red/white colony assay but also yeast-based screening assays developed during last year are discussed. Computational analysis and research carried out using yeast prions force us to expect that prions are widely present in nature. Indeed, the last few years brought us several examples indicating that the mammalian prion protein is no more peculiar protein - it seems that a better understanding of prion proteins nature-wide may aid us with the treatment of prion diseases and other amyloid-related medical conditions.
Since research on Creutzfeldt-Jakob disease, kuru, scrapie, and bovine spongiform encephalopathy-today all known to be caused by proteinaceous infectious particle, or prion-has accelerated half a century ago, various experimental models have been applied to investigate the nature of infectious agent as well as its transmission pathways. Now it is known that prion is the amyloid-type aggregate of prion protein (PrP) encoded by the PRNP gene in mammalian genomes. Mammalian PrP is known to appear in two distinct structural forms- PrPC (cellular, monomeric) and PrPSc (scrapie, with potential for amyloidogenesis). It is well-documented that PrPSc amyloids are the prion particles responsible for the transmission of prion diseases including Creutzfeldt-Jakob disease in humans or scrapie among sheep (Baral et al., 2019).
Amyloidogenesis is triggered by the structural conversion of PrPC into PrPSc. Although misfolded PrPSc is less stable than the native PrPC conformation, its secondary structure is enriched in [sz]-strands, which in turn can form cross-[sz] structure across a number of PrPSc molecules, in this way stabilizing each other. A similar phenomenon is observed for other amyloid-forming proteins that are responsible, in misfolded and aggregated forms, for the development of other neurological disorders like Alzheimer's, Parkinson's or Huntington's diseases (Almeida and Brito, 2020).
As the prion diseases have been identified in mammals, experimental models utilizing mammals have been used to...