Research

12 pages, 1954 KiB

Open AccessArticle

by Chih-Yen King

Viruses 2022, 14(11), 2337; https://doi.org/10.3390/v14112337 - 25 Oct 2022

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Prions replicate by a self-templating mechanism. Infidelity in the process can lead to the emergence of new infectious structures, referred to as variants or strains. The question of whether prions are prone to mis-templating is not completely answered. Our previous experiments with 23 [...] Read more.

Prions replicate by a self-templating mechanism. Infidelity in the process can lead to the emergence of new infectious structures, referred to as variants or strains. The question of whether prions are prone to mis-templating is not completely answered. Our previous experiments with 23 variants of the yeast [PSI⁺] prion do not support broad mutability. However, it became clear recently that the heat shock protein Hsp104 can restrict [PSI⁺] strain variation. This raises the possibility that many transmutable variants of the prion may have been mistaken as faithful-propagating simply because the mutant structure was too sturdy or too frail to take root in the wild-type cell. Here, I alter the strength of Hsp104 in yeast, overexpressing wild-type Hsp104 or expressing the hypo-active Hsp104^T160M mutant, and check if the new environments enable the variants to mutate. Two variants hitherto thought of as faithful-propagating are discovered to generate different structures, which are stabilized with the hypo-active chaperone. In contrast, most transmutable variants discovered in cells overexpressing Hsp104 have been correctly identified as such previously in wild-type cells without the overexpression. The majority of transmutable variants only mis-template the structure of VH, VK, or VL, which are the most frequently observed variants and do not spontaneously mutate. There are four additional variants that never give rise to different structures in all cell conditions tested. Therefore, quite a few [PSI⁺] variants are faithful-propagating, and even the transmutable ones do not freely evolve but can only change to limited structural types. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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12 pages, 2022 KiB

Open AccessArticle

Amino Acid Substitution within Seven-Octapeptide Repeat Insertions in the Prion Protein Gene Associated with Short-Term Course

by Zhongyun Chen, Haitian Nan, Yu Kong, Min Chu, Li Liu, Jing Zhang, Lin Wang and Liyong Wu

Viruses 2022, 14(10), 2245; https://doi.org/10.3390/v14102245 - 13 Oct 2022

Cited by 1 | Viewed by 1389

Abstract

The majority of seven-octapeptide repeat insertion (7-OPRI) carriers exhibit relatively early onset and a slowly progressive course. We have presented three cases of 7-OPRI, including two that are rapidly progressing, and compared the clinical and ancillary characteristics of the short-term and long-term disease [...] Read more.

The majority of seven-octapeptide repeat insertion (7-OPRI) carriers exhibit relatively early onset and a slowly progressive course. We have presented three cases of 7-OPRI, including two that are rapidly progressing, and compared the clinical and ancillary characteristics of the short-term and long-term disease course, as well as factors that influence disease course. The clinical and ancillary features of three new 7-OPRI patients in a Chinese pedigree were analyzed. Global data on 7-OPRI cases were then collected by reviewing the literature, and the cases were grouped according to clinical duration as per the WHO sCJD criteria, with a two-year cut-off. A Chinese pedigree has a glycine-to-glutamate substitution within the 7-OPRI insertion, which enhances the hydrophilicity of the prion protein. Two cases in this pedigree had a short disease course (consistent with the typical clinical and ancillary features of sCJD). In addition, the members of this pedigree had a later onset (p < 0.001) and shorter disease course (p < 0.001) compared to previously reported 7-OPRI cases with 129 cis-M and a similar age of onset and disease course to that of cases with 129 cis-V. The 7-OPRI cases with a shorter clinical course (n = 4) had a later onset (p = 0.021), higher rate of hyperintensity on MRI (p = 0.029) and higher frequency of 129 cis-V (p = 0.066) compared to those with a longer clinical course (n = 13). The clinical presentation of 7-OPRI is significantly heterogeneous. Codon 129 cis-V and amino acid substitution within repeat insertions are possible contributors to the short-term disease course of 7-OPRI. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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15 pages, 2193 KiB

Open AccessCommunication

Hsp40/JDP Requirements for the Propagation of Synthetic Yeast Prions

by Sarah C. Miller, Andrea K. Wegrzynowicz, Sierra J. Cole, Rachel E. Hayward, Samantha J. Ganser and Justin K. Hines

Viruses 2022, 14(10), 2160; https://doi.org/10.3390/v14102160 - 30 Sep 2022

Cited by 2 | Viewed by 1261

Abstract

Yeast prions are protein-based transmissible elements, most of which are amyloids. The chaperone protein network in yeast is inexorably linked to the spreading of prions during cell division by fragmentation of amyloid prion aggregates. Specifically, the core “prion fragmentation machinery” includes the proteins [...] Read more.

Yeast prions are protein-based transmissible elements, most of which are amyloids. The chaperone protein network in yeast is inexorably linked to the spreading of prions during cell division by fragmentation of amyloid prion aggregates. Specifically, the core “prion fragmentation machinery” includes the proteins Hsp104, Hsp70 and the Hsp40/J-domain protein (JDP) Sis1. Numerous novel amyloid-forming proteins have been created and examined in the yeast system and occasionally these amyloids are also capable of continuous Hsp104-dependent propagation in cell populations, forming synthetic prions. However, additional chaperone requirements, if any, have not been determined. Here, we report the first instances of a JDP-Hsp70 system requirement for the propagation of synthetic prions. We utilized constructs from a system of engineered prions with prion-forming domains (PrDs) consisting of a polyQ stretch interrupted by a single heterologous amino acid interspersed every fifth residue. These “polyQX” PrDs are fused to the MC domains of Sup35, creating chimeric proteins of which a subset forms synthetic prions in yeast. For four of these prions, we show that SIS1 repression causes prion loss in a manner consistent with Sis1′s known role in prion fragmentation. PolyQX prions were sensitive to Sis1 expression levels to differing degrees, congruent with the variability observed among native prions. Our results expand the scope known Sis1 functionality, demonstrating that Sis1 acts on amyloids broadly, rather than through specific protein–protein interactions with individual yeast prion-forming proteins. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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17 pages, 1609 KiB

Open AccessArticle

Implications of the Actin Cytoskeleton on the Multi-Step Process of [PSI⁺] Prion Formation

by Jane E. Dorweiler, Douglas R. Lyke, Nathan P. Lemoine, Samantha Guereca, Hannah E. Buchholz, Emily R. Legan, Claire M. Radtke and Anita L. Manogaran

Viruses 2022, 14(7), 1581; https://doi.org/10.3390/v14071581 - 21 Jul 2022

Cited by 2 | Viewed by 1657

Abstract

Yeast prions are self-perpetuating misfolded proteins that are infectious. In yeast, [PSI⁺] is the prion form of the Sup35 protein. While the study of [PSI⁺] has revealed important cellular mechanisms that contribute to prion propagation, the underlying [...] Read more.

Yeast prions are self-perpetuating misfolded proteins that are infectious. In yeast, [PSI⁺] is the prion form of the Sup35 protein. While the study of [PSI⁺] has revealed important cellular mechanisms that contribute to prion propagation, the underlying cellular factors that influence prion formation are not well understood. Prion formation has been described as a multi-step process involving both the initial nucleation and growth of aggregates, followed by the subsequent transmission of prion particles to daughter cells. Prior evidence suggests that actin plays a role in this multi-step process, but actin’s precise role is unclear. Here, we investigate how actin influences the cell’s ability to manage newly formed visible aggregates and how actin influences the transmission of newly formed aggregates to future generations. At early steps, using 3D time-lapse microscopy, several actin mutants, and Markov modeling, we find that the movement of newly formed aggregates is random and actin independent. At later steps, our prion induction studies provide evidence that the transmission of newly formed prion particles to daughter cells is limited by the actin cytoskeletal network. We suspect that this limitation is because actin is used to possibly retain prion particles in the mother cell. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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13 pages, 2144 KiB

Open AccessArticle

Identifying Endogenous Cellular Proteins Destabilizing the Propagation of Swi1 Prion upon Overproduction

by Zhiqiang Du, Brandon Cho and Liming Li

Viruses 2022, 14(7), 1366; https://doi.org/10.3390/v14071366 - 23 Jun 2022

Viewed by 1349

Abstract

(1) Background: Numerous prions exist in the budding yeast, including [SWI⁺], the prion form of Swi1—a subunit of the chromatin-remodeling complex SWI/SNF. Despite decades of research, the molecular mechanisms underlying prion initiation and propagation are not fully understood. In this [...] Read more.

(1) Background: Numerous prions exist in the budding yeast, including [SWI⁺], the prion form of Swi1—a subunit of the chromatin-remodeling complex SWI/SNF. Despite decades of research, the molecular mechanisms underlying prion initiation and propagation are not fully understood. In this study, we aimed to identify endogenous cellular proteins that destabilize [SWI⁺]. (2) Methods: We screened the MoBY-ORF 2.0 library for proteins that destabilize [SWI⁺] upon overproduction. We further explored the effects of the identified candidates against other yeast prions and analyzed their potential prion-curing mechanisms. (3) Results: Eighty-two [SWI⁺] suppressors were identified, and their effects were shown to be [SWI⁺]-specific. Interestingly, a few documented [SWI⁺] suppressors were not among the identified hits. Further experiments indicate that, for some of these [SWI⁺] suppressors, their overproduction, and thus their prion-curing activities, are regulated by environmental conditions. Bioinformatics analyses show that our identified [SWI⁺] suppressors are involved in diverse biological functions, with gene ontology term enrichments specifically for transcriptional regulation and translation. Competition for Swi1 monomers between [SWI⁺] and Swi1 interactors, including the SWI/SNF complex, is a potential prion-curing mechanism. (4) Conclusions: We identified a number of [SWI⁺]-specific suppressors that highlight unique features of [SWI⁺] in maintaining its self-perpetuating conformations. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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11 pages, 2187 KiB

Open AccessArticle

Novel Polymorphisms and Genetic Characteristics of the Shadow of Prion Protein Gene (SPRN) in Cats, Hosts of Feline Spongiform Encephalopathy

by Yong-Chan Kim, Hyeon-Ho Kim, Kiwon Kim, An-Dang Kim and Byung-Hoon Jeong

Viruses 2022, 14(5), 981; https://doi.org/10.3390/v14050981 - 06 May 2022

Cited by 1 | Viewed by 1460

Abstract

Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by pathogenic prion protein (PrP^Sc) originating from normal prion protein (PrP^C) and have been reported in several types of livestock and pets. Recent studies have reported that the shadow of prion [...] Read more.

Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by pathogenic prion protein (PrP^Sc) originating from normal prion protein (PrP^C) and have been reported in several types of livestock and pets. Recent studies have reported that the shadow of prion protein (Sho) encoded by the shadow of prion protein gene (SPRN) interacts with prion protein (PrP) and accelerates prion diseases. In addition, genetic polymorphisms in the SPRN gene are related to susceptibility to prion diseases. However, genetic polymorphisms in the feline SPRN gene and structural characteristics of the Sho have not been investigated in cats, a major host of feline spongiform encephalopathy (FSE). We performed amplicon sequencing to identify feline SPRN polymorphisms in the 623 bp encompassing the open reading frame (ORF) and a small part of the 3′ untranslated region (UTR) of the SPRN gene. We analyzed the impact of feline SPRN polymorphisms on the secondary structure of SPRN mRNA using RNAsnp. In addition, to find feline-specific amino acids, we carried out multiple sequence alignments using ClustalW. Furthermore, we analyzed the N-terminal signal peptide and glycosylphosphatidylinositol (GPI)-anchor using SignalP and PredGPI, respectively. We identified three novel SNPs in the feline SPRN gene and did not find strong linkage disequilibrium (LD) among the three SNPs. We found four major haplotypes of the SPRN polymorphisms. Strong LD was not observed between PRNP and SPRN polymorphisms. In addition, we found alterations in the secondary structure and minimum free energy of the mRNA according to the haplotypes in the SPRN polymorphisms. Furthermore, we found four feline-specific amino acids in the feline Sho using multiple sequence alignments among several species. Lastly, the N-terminal signal sequence and cutting site of the Sho protein of cats showed similarity with those of other species. However, the feline Sho protein exhibited the shortest signal sequence and a unique amino acid in the omega-site of the GPI anchor. To the best of our knowledge, this is the first report on genetic polymorphisms of the feline SPRN gene. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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Review

Jump to: Research, Other

11 pages, 782 KiB

Open AccessReview

Anti-Prion Systems in Saccharomyces cerevisiae Turn an Avalanche of Prions into a Flurry

by Moonil Son and Reed B. Wickner

Viruses 2022, 14(9), 1945; https://doi.org/10.3390/v14091945 - 01 Sep 2022

Cited by 2 | Viewed by 2148

Abstract

Prions are infectious proteins, mostly having a self-propagating amyloid (filamentous protein polymer) structure consisting of an abnormal form of a normally soluble protein. These prions arise spontaneously in the cell without known reason, and their effects were generally considered to be fatal based [...] Read more.

Prions are infectious proteins, mostly having a self-propagating amyloid (filamentous protein polymer) structure consisting of an abnormal form of a normally soluble protein. These prions arise spontaneously in the cell without known reason, and their effects were generally considered to be fatal based on prion diseases in humans or mammals. However, the wide array of prion studies in yeast including filamentous fungi revealed that their effects can range widely, from lethal to very mild (even cryptic) or functional, depending on the nature of the prion protein and the specific prion variant (or strain) made by the same prion protein but with a different conformation. This prion biology is affected by an array of molecular chaperone systems, such as Hsp40, Hsp70, Hsp104, and combinations of them. In parallel with the systems required for prion propagation, yeast has multiple anti-prion systems, constantly working in the normal cell without overproduction of or a deficiency in any protein, which have negative effects on prions by blocking their formation, curing many prions after they arise, preventing prion infections, and reducing the cytotoxicity produced by prions. From the protectors of nascent polypeptides (Ssb1/2p, Zuo1p, and Ssz1p) to the protein sequesterase (Btn2p), the disaggregator (Hsp104), and the mysterious Cur1p, normal levels of each can cure the prion variants arising in its absence. The controllers of mRNA quality, nonsense-mediated mRNA decay proteins (Upf1, 2, 3), can cure newly formed prion variants by association with a prion-forming protein. The regulator of the inositol pyrophosphate metabolic pathway (Siw14p) cures certain prion variants by lowering the levels of certain organic compounds. Some of these proteins have other cellular functions (e.g., Btn2), while others produce an anti-prion effect through their primary role in the normal cell (e.g., ribosomal chaperones). Thus, these anti-prion actions are the innate defense strategy against prions. Here, we outline the anti-prion systems in yeast that produce innate immunity to prions by a multi-layered operation targeting each step of prion development. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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20 pages, 1684 KiB

Open AccessReview

Recombinant Mammalian Prions: The “Correctly” Misfolded Prion Protein Conformers

by Jiyan Ma, Jingjing Zhang and Runchuan Yan

Viruses 2022, 14(9), 1940; https://doi.org/10.3390/v14091940 - 31 Aug 2022

Cited by 1 | Viewed by 2186

Abstract

Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to [...] Read more.

Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to elicit a fatal neurodegenerative disorder in wild-type animals like a naturally occurring prion. The application of the protein misfolding cyclic amplification technique and the inclusion of non-protein cofactors in the reaction mixture have led to the generation of authentic recombinant prions that fully recapitulate the characteristics of native prions. Together, these studies reveal that recPrP can stably exist in a variety of misfolded conformations and when inoculated into wild-type animals, misfolded recPrP conformers cause a wide range of outcomes, from being completely innocuous to lethal. Since all these recPrP conformers possess seeding capabilities, these results clearly suggest that seeding activity alone is not equivalent to prion activity. Instead, authentic prions are those PrP conformers that are not only heritable (the ability to seed the conversion of normal PrP) but also pathogenic (the ability to cause fatal neurodegeneration). The knowledge gained from the studies of the recombinant prion is important for us to understand the pathogenesis of prion disease and the roles of misfolded proteins in other neurodegenerative disorders. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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20 pages, 1303 KiB

Open AccessReview

Beyond Amyloid Fibers: Accumulation, Biological Relevance, and Regulation of Higher-Order Prion Architectures

by Wesley R. Naeimi and Tricia R. Serio

Viruses 2022, 14(8), 1635; https://doi.org/10.3390/v14081635 - 27 Jul 2022

Cited by 5 | Viewed by 2319

Abstract

The formation of amyloid fibers is associated with a diverse range of disease and phenotypic states. These amyloid fibers often assemble into multi-protofibril, high-order architectures in vivo and in vitro. Prion propagation in yeast, an amyloid-based process, represents an attractive model to explore [...] Read more.

The formation of amyloid fibers is associated with a diverse range of disease and phenotypic states. These amyloid fibers often assemble into multi-protofibril, high-order architectures in vivo and in vitro. Prion propagation in yeast, an amyloid-based process, represents an attractive model to explore the link between these aggregation states and the biological consequences of amyloid dynamics. Here, we integrate the current state of knowledge, highlight opportunities for further insight, and draw parallels to more complex systems in vitro. Evidence suggests that high-order fibril architectures are present ex vivo from disease relevant environments and under permissive conditions in vivo in yeast, including but not limited to those leading to prion formation or instability. The biological significance of these latter amyloid architectures or how they may be regulated is, however, complicated by inconsistent experimental conditions and analytical methods, although the Hsp70 chaperone Ssa1/2 is likely involved. Transition between assembly states could form a mechanistic basis to explain some confounding observations surrounding prion regulation but is limited by a lack of unified methodology to biophysically compare these assembly states. Future exciting experimental entryways may offer opportunities for further insight. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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Other

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9 pages, 1067 KiB

Open AccessBrief Report

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

by Sei-Kyoung Park, Sangeun Park and Susan W. Liebman

Viruses 2022, 14(10), 2264; https://doi.org/10.3390/v14102264 - 15 Oct 2022

Cited by 3 | Viewed by 1496

Abstract

When human TDP-43 is overexpressed in yeast it is toxic and forms cytoplasmic aggregates. The mechanism of this toxicity is unknown. Genetic screens for TDP-43 toxicity modifiers in the yeast system previously identified proteins, including PBP1, that enhance TDP-43 toxicity. The determination in [...] Read more.

When human TDP-43 is overexpressed in yeast it is toxic and forms cytoplasmic aggregates. The mechanism of this toxicity is unknown. Genetic screens for TDP-43 toxicity modifiers in the yeast system previously identified proteins, including PBP1, that enhance TDP-43 toxicity. The determination in yeast that deletion of PBP1 reduces TDP-43 toxicity while overexpression enhances toxicity, led to the discovery that its human homolog, ATXN2, is associated with ALS risk. Thus, the yeast system has relevance to human disease. We now show that deletion of a new yeast gene, tip41Δ, likewise suppresses TDP-43 toxicity. We also found that TDP-43 overexpression and toxicity is associated with reduced autophagy. This is consistent with findings in other systems that increasing autophagy reduces TDP-43 toxicity and is in contrast to a report of enhanced autophagy when TDP-43 was overexpressed in yeast. Interestingly, we found that deletions of PBP1 and TIP41, which reduced TDP-43 toxicity, eliminated TDP-43′s inhibition of autophagy. This suggests that toxicity of TDP-43 expressed in yeast is in part due to its inhibition of autophagy and that deletions of PBP1 and TIP41 may reduce TDP-43 toxicity by preventing TDP-43 from inhibiting autophagy. Full article

(This article belongs to the Special Issue Prions and Prion-Like Phenomena: Appearance, Inheritance and Importance)

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