Transmissible spongiform encephalopathies (TSEs), also called prion diseases, attracted attention after the “mad cow” disease outbreak in Europe in the 1990s, although other examples of these diseases, such as sheep scrapie, human Creutzfeldt-Jacob disease, etc. were known long ago (for review, see [1
]). A most unusual feature of these diseases is that infection is transmitted not by bacteria or viruses, but by protein-based infectious particles (termed prions). The “protein only” model of TSE transmission, accepted by most researchers in the field, postulates that a specific mammalian protein (named PrP) in an abnormal (“prion”) shape becomes an infectious agent as it acquires an ability to convert the normally folded host protein of the same sequence into a prion shape. According to one of the modifications of the prion model, the prion isoform of PrP represents an ordered aggregate that can proliferate by immobilizing the soluble PrP molecules [2
]. Indeed, PrP generates fibrous β-rich ordered aggregates (called amyloids) in the brains of infected animals [1
Amyloids formed by PrP resemble non-infectious amyloids or amyloid-like aggregates associated with some other diseases, including such neurodegenerative disorders as Alzheimer disease (AD), Huntington disease (HD), Parkinson disease (PD), etc. (for review, see [3
]). Some of these diseases are caused by mutations, e. g. by expansions of a polyglutamine (poly-Q) stretch in a protein called huntingtin, in case of HD. Other diseases (e. g. most cases of AD) occur sporadically, so that triggering mechanisms remain unknown. Some amyloidoses (including AD) are clearly age-dependent, pointing to a potential connection between amyloid formation and aging. Therefore, the importance of these diseases grows dramatically with eradication of other diseases and increase of life expectancy in the human populations. It is worth mentioning that prion diseases and many other amyloidoses (including AD and HD) remain fatal and incurable thus far. Without any exaggeration, it is easy to forecast that AD and similar disorders have a potential of becoming the major cause of death for the next generations of humans.
Lower eukaryotes, such as yeast and other fungi, also contain self-perpetuating transmissible amyloids that possess prion-like properties (for review, see [4
]). These amyloids manifest themselves as non-Mendelian elements that control specific traits, heritable in cell generations and infectious via cytoplasmic exchange. Although fungal amyloid-forming proteins are not homologous to mammalian PrP, they are also usually termed “prion proteins”. Fungal prions do not necessarily kill their carriers. However, recent data demonstrate that at least some fungal prions are pathogenic to a certain extent (reviewed in [4
In the yeast Saccharomyces cerevisiae
, several proteins have been proven to generate self-perpetuating amyloid-based prions. These include: 1) translational termination factor Sup35 (also called eRF3); 2) regulatory protein in the nitrogen metabolism pathway, Ure2; 3) protein of unknown function, Rnq1 (for review, see [4
]). Prion forms of these proteins are termed [PSI+
], [URE3] and [PIN+
] (or [RNQ+
]), respectively. Yeast prion proteins contain N-terminal or C-terminal regions, termed prion domains or PrDs, that are required and sufficient for prion formation and propagation, and are dispensable for the normal cellular function of a prion protein in cases when this function is known (for review, see [5
]). While known yeast prion proteins are not homologous to each other, they contain common sequence elements, some of which also resemble certain regions of mammalian amyloidogenic proteins. For example, all known yeast PrDs contain QN-rich stretches that are similar to the poly-Q stretch of mammalian huntingtin, and some yeast PrDs contain oligopeptide repeats (ORs) similar to those found in mammalian PrP (reviewed in [4
]). Mechanisms of amyloid formation in yeast and other fungi appear to be very similar to those described in mammalian systems. Therefore, yeast prions provide easy and efficient experimental assays for studying the factors and conditions influencing amyloid formation and propagation.
As amyloids are protein aggregates, the question arises whether cellular defense systems aimed at protecting the cells from aggregation of stress-damaged proteins can also recognize amyloids. This review summarizes data, obtained in the yeast models, that implicate stress-related proteins as major modulators of amyloid formation and propagation in a eukaryotic cell.