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This editorial explores the concept of prions, which are proteins that can adopt unconventional conformations and pass these conformations to other proteins. Prions have been associated with various human diseases and have been found in different species, including yeast. The document includes multiple articles that delve into various aspects of prion biology, such as the formation, propagation, and elimination of prions in yeast cells. It also discusses the role of chaperones and other cellular systems in regulating prion formation and propagation. The text highlights the importance of using different experimental approaches to understand the nature and impact of in vivo aggregates. The articles cover topics such as the study of human proteins in yeast, genetic prion diseases, and the analysis of the shadow of prion protein gene in cats. The authors express gratitude to the contributors and reviewers and emphasize the need for further research to develop disease treatment strategies and drug development. They also mention the ongoing discussion about the transmission of prion diseases to humans and the potential role of plants in environmental transmission. [Extracted from the article]

Prions are infectious protein conformations that are generally ordered protein aggregates. In the absence of prions, newly synthesized molecules of these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without a homologous prion template. The conformational switch that results in the de novo appearance of yeast prions with glutamine/aspargine (Q/N)-rich prion domains (e.g., [PS[I.sup.+]]), is promoted by heterologous prions with a similar domain (e.g., [RN[Q.sup.+]], also known as [PI[N.sup.+]]), or by overexpression of proteins with prion-like Q-, N-, or Q/N-rich domains. This finding led to the hypothesis that aggregates of heterologous proteins provide an imperfect template on which the new prion is seeded. Indeed, we show that newly forming Sup35 and preexisting Rnq1 aggregates always colocalize when [PS[I.sup.+]] appearance is facilitated by the [RN[Q.sup.+]] prion, and that Rnq1 fibers enhance the in vitro formation of fibers by the prion domain of Sup35 (NM). The proteins do not however form mixed, interdigitated aggregates. We also demonstrate that aggregating variants of the polyQ-containing domain of huntingtin promote the de novo conversion of Sup35 into [PS[I.sup.+]]; whereas nonaggregating variants of huntingtin and aggregates of non-polyQ amyloidogenic proteins, transthyretin, [alpha]-synuclein, and synphilin do not. Furthermore, transthyretin and [alpha]-synuclein amyloids do not facilitate NM aggregation in vitro, even though in [PS[I.sup.+]] cells NM and transthyretin aggregates also occasionally colocalize. Our data, especially the in vitro reproduction of the highly specific heterologous seeding effect, provide strong support for the hypothesis of cross-seeding in the spontaneous initiation of prion states.

The yeast Sup35 and Rnq1 proteins can exist in either the noninfectious soluble forms, [[psi.sup.-]] or [[pin.sup.-]], respectively, or the multiple infectious amyloid-like forms called [PS[I.sup.+]] or [PI[N.sup.+]] prion variants (or prion strains). It was previously shown that [PS[I.sup.+]] and [PI[N.sup.+]] prions enhance one another's de novo appearance. Here we show that specific prion variants of [PS[I.sup.+]] and [PI[N.sup.+]] disrupt each other's stable inheritance. Acquiring [PS[I.sup.+]] often impedes the inheritance of particular [PI[N.sup.+]] variants. Conversely, the presence of some [PI[N.sup.+]] variants impairs the inheritance of weak [PS[I.sup.+]] but not strong [PS[I.sup.+]] variants. These same [PI[N.sup.+]] variants generate a single-dot fluorescence pattern when a fusion of Rnq1 and green fluorescent protein is expressed. Another [PI[N.sup.+]] variant, which forms a distinctly different multiple-dot fluorescence pattern, does not impair [PS[I.sup.+]] inheritance. Thus, destabilization of prions by heterologous prions depends upon the variants involved. These findings may have implications for understanding interactions among other amyloid-forming proteins, including those associated with certain human diseases.

Results reveal that formation of new prions is enhanced by heterologous prion aggregates as evidenced by the de novo appearance of Rnq1::GFP prion aggregates requiring the presence of other prions. Furthermore, the yeast non-Mendelian trait [PIN(sup)+] forms [PSI(sup)+] prion.

Research has been conducted on the Saccharomyces cerevisiae mutant strains. The use of these strains in studying ribosomal structure and function is discussed.

[[PSI.sup.+]], a non-Mendelian element found in some strains of Saccharomyces cerevisiae, is presumed to be the manifestation of a self-propagating prion conformation of eRF3 (Sup35p). Translation termination factor eRF3 enhances the activity of release factor eRF1 (Sup45p). As predicted by the prion model, overproduction of Sup35p induces the de novo appearance of [[PSI.sup.+]]. However, another nonMendelian determinant, [[PIN.sup.+]], is required for this induction. We now show that SUP45 overexpression inhibits the induction of [[PSI.sup.+]] by Sup35p overproduction in [[PIN.sup.+]] strains, but has no effect on the propagation of [[PSI.sup.+]] or on the [PLN] status of the cells. We also show that SUP45 overexpression counteracts the growth inhibition usually associated with overexpression of SUP35 in [[PSI.sup.+]] strains. We argue that excess Sup45p inhibits [[PSI.sup.+]] seed formation. Because Sup45p complexes with Sup35p, we hypothesize that excess Sup45p may sequester Sup35p, thereby reducing the opportunity for Sup35p conformational flips and/or self-interactions leading to prion formation. This in vivo yeast result is reminiscent of the in vitro finding by investigators of Alzheimer disease that apolipoprotein E inhibits amyloid nucleation, but does not reduce seeded growth of amyloid.

It has previously been shown that yeast prion [[PSI.sup.+]] is cured by GuHCl, although reports on reversibility of curing were contradictory. Here we show that GuHCl treatment of both [[PSI.sup.+]] and [[psi.sup.-]] yeast strains results in two classes of [[psi.sup.-]] derivatives: [Pin.sup.+], in which [[PSI.sup.+]] can be reinduced by Sup35p overproduction, and [Pin.sup.-], in which overexpression of the complete SUP35 gene does not lead to the [[PSI.sup.+]] appearance. However, in both [Pin.sup.+] and [Pin.sup.-] derivatives [[PSI.sup.+]] is reinduced by overproduction of a short Sup35p N-terminal fragment, thus, in principle, [[PSI.sup.+]] curing remains reversible in both cases. Neither suppression nor growth inhibition caused by SUP35 overexpression in [Pin.sup.+] [[psi.sup.-]] derivatives are observed in [Pin.sup.-] [[psi.sup.-]] derivatives. Genetic analyses show that the [Pin.sup.+] phenotype is determined by a non-Mendelian factor, which, unlike the [[PSI.sup.+]] prion, is independent of the Sup35p N-terminal domain. A [Pin.sup.-] [[psi.sub.-]] derivative was also generated by transient inactivation of the heat shock protein, Hsp104, while [[PSI.sub.+]] curing by Hsp104 overproduction resulted exclusively in [Pin.sub.+] [[psi.sup.-]] derivatives. We hypothesize that in addition to the [[PSI.sup.+]] prion-determining domain in the Sup35p N-terminus, there is another self-propagating conformational determinant in the C-proximal part of Sup35p and that this second prion is responsible for the [Pin.sup.+] phenotype.

We have previously shown that multicopy plasmids containing the complete SUP35 gene are able to induce the appearance of the non-Mendelian factor [PSI]. This result was later interpreted by others as a crucial piece of evidence for a model postulating that [PSI] is a self-modified, prion-like conformational derivative of the Sup35 protein. Here we support this interpretation by proving that it is the overproduction of Sup35 protein, and not the excess of SUP35 DNA or mRNA that causes the appearance of [PSI]. We also show that the 'prion-inducing domain' of Sup35p is in the N-terminal region, which, like the 'prion-inducing domain' of another yeast prion, Ure2p, was previously shown to be distinct from the functional domain of the protein. This suggests that such a chimeric organization may be a common pattern of some prion elements. Finally, we find that [PSI] factors of different efficiencies and different mitotic stabilities are induced in the same yeast strain by overproduction of the identical Sup35 protein. We suggest that the different [PSI]-containing derivatives are analogous to the mysterious mammalian prion strains and result from different conformational variants of Sup35p.

Complementation of sal6-1-induced cold sensitivity and improved suppression capacity in the presence of suppressor sup45 enable the cloning of the SAL6 gene with a large N-terminus rich in serine and a C-terminal similar to type 1 serine/threonine protein phosphatases. The open reading frame of SAL6, which is mapped to chromosome XVI between spt14 and TPK2, codes for a basic protein with a 549 amino acid sequence. SAL6 undergoes potent disruptions, leading to a minimal defect in growth on glycerol medium and the formation of allosuppressor phenotypes. The number of active SAL6 genes in a cell determines the translational accuracy of the cell.

The effect of mutations in rad6, the gene encoding the ubiquitin-conjugating enzyme RAD6, on target site preferences of the yeast transposons Ty1 and Ty2 was assessed. The 53 independent Ty1 and Ty2 insertions isolated in an isogenic rad6 deletion strain did not show the conventional gradient of insertion frequency, rather, the Ty elements were inserted randomly throughout the CAN1 gene. Thus, the ubiquitin-conjugating enzyme, RAD6, alters the integration site preferences of Ty1 retrotransposons.

SUP46, a translation suppressor, encodes the S13 ribosomal protein in yeasts. The ribosomal protein is encoded by two other genes but only SUP46 can complement recessive strains with mutations in the sup46. SUP46 bears significant homology to the product of one of the ribosomal ambiguity genes in Escherichia coli, S4, the equivalent of omnipotent suppressors in prokaryotes. The homology is most pronounced within the central region of the two proteins alterations in which affects binding of the 16S ribosomal RNA.

Structural description of two uncommon deletions in the genome of Saccharomyces cerevisiae is presented. The deletions range from a Ty1 retrotransposon ending in a region near multiple copies of glycine tRNA. Unique sequences bordered by two repetitive elements or flanked by a transposable element are mobile within the genome. Models explaining the generation of these deletions were evaluated by analysis of 32 isolated deletions in the CYC1 segment.

Abstract Background Prions are self-perpetuating, infectious, aggregated proteins that are associated with several neurodegenerative diseases in mammals and heritable traits in yeast. Sup35p, the protein determinant of the yeast prion [PSI+], has a conserved C terminal domain that performs the Sup35p function and a prion domain that is highly divergent. Prions formed by chimeras of the prion domain of various species fused to the C domain of Saccharomyces cerevisiae exhibit a 'species barrier', a phenomenon first observed in mammals, and often fail to transmit the prion state to chimeras with prion domains of other species. Results We focus on the chimera containing the prion domain of Pichia methanolica and examine how tight the 'species barrier' is between the chimera and S. cerevisiae. Although either of two Q/N-rich prions, [PSI+] or [PIN+], enhances the formation of the chimeric prion, [CHI+PM], neither a non-Q/N-rich prion nor a non-prion Q-rich aggregate promotes the formation of [CHI+PM]. [CHI+PM] has many features characteristic of yeast prions: aggregation, cytoplasmic transmission and a two-level protein structure. [CHI+PM] formed in the presence of [PSI+] can propagate independently of [PSI+] and forms at least two different variants of the prion, suggesting the generation and not transmission of new prion seeds. Conclusion Although the sequence similarity between the S. cerevisiae Q/N-rich prion determinants and the P. methanolica prion domain is low, we find that the chimera containing the prion domain of P. methanolica can occasionally be cross-seeded by [PSI+] to mimic crossing the species barrier, to form the [CHI+PM] prion. Our data suggests that crossing the barrier occurs by a de novo formation of the foreign chimeric prion. Thus, the species barrier appears to be crossed by a heterologous seeding mechanism, wherein the infected prion protein uses the pre-existing seed as an inefficient template.