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

Wickner, Reed B.; Edskes, Herman K.; Bateman, David A.; Kelly, Amy C.; Gorkovskiy, Anton

doi:10.4161/pri.5.4.17748

Cited by 18 publications

(21 citation statements)

References 32 publications

(42 reference statements)

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“…Thus, some authors have suggested that prions are adaptive bet-hedging devices or evolutionary capacitors that empower survival in intermittently stressful and fluctuating environments (Halfmann et al, 2010; Halfmann and Lindquist, 2010; Lancaster et al, 2010; Masel and Bergman, 2003; Masel and Griswold, 2009; Shorter and Lindquist, 2005; Shorter, 2010; Tuite and Serio, 2010). Conversely, others contend that yeast prions are molecular degenerative diseases more akin to mammalian neurodegenerative disorders (Wickner et al, 2007; Wickner et al, 2011). However, the fact that yeast prions can confer strong selective advantages under defined conditions separates them from simple degenerative disorders that are invariably deleterious.…”

Section: Yeast Prions: Good or Evil Or Both?mentioning

confidence: 99%

The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease

2012

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Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer’s disease and Huntington’s disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion-like domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system.

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Section: Yeast Prions: Good or Evil Or Both?mentioning

confidence: 99%

The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease

2012

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“…1 In the budding yeast Saccharomyces cerevisiae several different proteins can propagate alternative conformations via a prion-like mechanism and thus serve as epigenetic switches that produce heritable phenotypes. 2 Although it has been suggested that yeast prions represent disease states, [3][4][5][6] the evolution of prion domains in a variety of yeast proteins and the occurrence of prions in wild yeast populations raise the possibility that such a mechanism may also have important biological roles. 7,8 A well-studied example is the [PSI C ] prion, which is a selfpropagating amyloid form of the translation termination factor Sup35.…”

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confidence: 99%

The ribosome-associated complex antagonizes prion formation in yeast

Amor

Castanzo

Delany

et al. 2015

Prion

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ABSTRACT. The number of known fungal proteins capable of switching between alternative stable conformations is steadily increasing, suggesting that a prion-like mechanism may be broadly utilized as a means to propagate altered cellular states. To gain insight into the mechanisms by which cells regulate prion formation and toxicity we examined the role of the yeast ribosome-associated complex (RAC) in modulating both the formation of the [PSI C ] prion -an alternative conformer of Sup35 protein -and the toxicity of aggregation-prone polypeptides. The Hsp40 RAC chaperone Zuo1 anchors the RAC to ribosomes and stimulates the ATPase activity of the Hsp70 chaperone Ssb. We found that cells lacking Zuo1 are sensitive to over-expression of some aggregation-prone proteins, including the Sup35 prion domain, suggesting that co-translational protein misfolding increases in Dzuo1 strains. Consistent with this finding, Dzuo1 cells exhibit higher frequencies of spontaneous and induced prion formation. Cells expressing mutant forms of Zuo1 lacking either a C-terminal charged region required for ribosome association, or the J-domain responsible for Ssb ATPase stimulation, exhibit similarly high frequencies of prion formation. Our findings are consistent with a role for the RAC in chaperoning nascent Sup35 to regulate folding of the N-terminal prion domain as it emerges from the ribosome.

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“…Most yeast prions are intracellular amyloids inherited in a nonMendelian fashion (via cytoplasm) and containing QN-rich prion domains that resemble mammalian proteins associated with polyglutamine disorders such as Huntington's disease. Some yeast prions are pathogenic to the yeast "host" (41,68), thus establishing yeast as a model for studying the pathogenic amyloids. Other yeast prions are widespread in nature, pointing to potentially positive biological effects (23).…”

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confidence: 99%