The yeast prions [PSI+] and [URE3] are molecular degenerative diseases

Abstract

The yeast prions [URE3] and [PSI] are not found in wild strains, suggesting they are not an advantage. Prion-forming ability is not conserved, even within Saccharomyces, suggesting it is a disease. Prion domains have non-prion functions, explaining some conservation of sequence. However, in spite of the sequence being constrained in evolution by these non-prion functions, the prion domains vary more rapidly than the remainder of the molecule, and these changes produce a transmission barrier, suggesting that these changes were selected to block prion infection. Yeast prions [PSI] and [URE3] induce a cellular stress response (Hsp104 and Hsp70 induction), suggesting the cells are not happy about being infected. Recently, we showed that the array of [PSI] and [URE3] prions includes a majority of lethal or very toxic variants, a result not expected if either prion were an adaptive cellular response to stress.

Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease

“…Yeast prions can confer selective advantages in various circumstances, but can also be neutral or detrimental in other settings (Du et al, 2015; Halfmann et al, 2012; Holmes et al, 2013; Newby and Lindquist, 2013; Shorter and Lindquist, 2005; Suzuki et al, 2012; Wickner et al, 2011). The beneficial phenotypes conferred by yeast prions are often observed under stress conditions, which has led to the suggestion that yeast prions constitute bet-hedging devices, which can reveal potentially adaptive genetic diversity in fluctuating environments (Du et al, 2015; Garcia and Jarosz, 2014; Halfmann et al, 2010; Halfmann and Lindquist, 2010; Masel and Bergman, 2003; Newby and Lindquist, 2013; Tyedmers et al, 2008).…”

“…The adaptive significance of yeast prions, particularly Sup35 prions, has been contested (McGlinchey et al, 2011; Nakayashiki et al, 2005; Wickner et al, 2011, 2015). There has been a lack of evidence that Sup35 and Ure2 prions arise in wild yeast (although Rnq1 prions were readily found) (Chernoff et al, 2000; Resende et al, 2003), leading to speculation that prions were merely ‘diseases’ or artifacts of laboratory cultivation (Wickner et al, 2011, 2015).…”

“…There has been a lack of evidence that Sup35 and Ure2 prions arise in wild yeast (although Rnq1 prions were readily found) (Chernoff et al, 2000; Resende et al, 2003), leading to speculation that prions were merely ‘diseases’ or artifacts of laboratory cultivation (Wickner et al, 2011, 2015). However, a survey of 690 wild yeast strains from diverse biological niches found 10 strains harboring Sup35 prions, 43 harboring Rnq1 prions, and 6 harboring Mot3 prions (Halfmann et al, 2012).…”

Life cycle of cytosolic prions

“…Yeast prions constitute protein-based epigenetic elements that confer heritable phenotypic traits to their hosts 8 , 9 . At least nine different prion proteins of fungi have been identified that can be lethal or beneficial to the host 10 - 12 . Yeast prions are predominately cytoplasmic, with one exception that resides within the nucleus 13 .…”

Yeast prions and human prion-like proteins: sequence features and prediction methods

“…Some argue that prions may be advantageous to yeast under particular conditions, allowing them to act as means of survival and adaption in fluctuating environments [12–14]. Others maintain that, since yeast prions are relatively rare in wild strains despite their ability to form spontaneously and spread, these prions likely do not confer a selective advantage [15–18]. Rather, yeast PFDs may have evolved for reasons unrelated to prion formation.…”