Neurodegenerative amyloidoses: Yeast model

Ab, Vishnevskaia; Vv, Kushnirov; Ter-Avanesian,

doi:10.1134/s0026893307020112

Cited by 10 publications

(4 citation statements)

References 53 publications

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“…In mammals, amyloids may accumulate in the brain and cause various neurodegenerative diseases, such as transmissible spongiform encephalopathies (TSEs), characterized by deposits of the human prion protein (PrP) in the self-propagating amyloid form (PrP sc ). In the yeast Saccharomyces cerevisiae, a convenient model to study various amyloidoses (Vishnevskaia et al, 2007), the non-Mendelian genetic elements [PSI ϩ ], [URE3], and [PIN ϩ ] were shown to be self-propagating conformations (i.e., prions) of the Sup35, Ure2, and Rnq1 proteins, respectively (for review, see Wickner et al, 2007). Variations in the conformation of the infectious PrP sc amyloids are thought to underlie the existence of prion "strains" that cause different forms of prion diseases (for review, see Bruce, 2003).…”

Section: Introductionmentioning

confidence: 99%

Variant-specific [PSI⁺] Infection Is Transmitted by Sup35 Polymers within [PSI⁺] Aggregates with Heterogeneous Protein Composition

Bagriantsev

Gracheva

Richmond

et al. 2008

MBoC

121

149

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The [PSI(+)] prion is the aggregated self-propagating form of the Sup35 protein from the yeast Saccharomyces cerevisiae. Aggregates of Sup35 in [PSI(+)] cells exist in different heritable conformations, called "variants," and they are composed of detergent-resistant Sup35 polymers, which may be closely associated with themselves, other proteins, or both. Here, we report that disassembly of the aggregates into individual Sup35 polymers and non-Sup35 components increases their infectivity while retaining their variant specificity, showing that variant-specific [PSI(+)] infection can be transmitted by Sup35 polymers alone. Morphological analysis revealed that Sup35 isolated from [PSI(+)] yeast has the appearance of short barrels, and bundles, which seem to be composed of barrels. We show that the major components of two different variants of [PSI(+)] are interacting infectious Sup35 polymers and Ssa1/2. Using a candidate approach, we detected Hsp104, Ssb1/2, Sis1, Sse1, Ydj1, and Sla2 among minor components of the aggregates. We demonstrate that Ssa1/2 efficiently binds to the prion domain of Sup35 in [PSI(+)] cells, but that it interacts poorly with the nonaggregated Sup35 found in [psi(-)] cells. Hsp104, Sis1, and Sse1 interact preferentially with the prion versus nonprion form of Sup35, whereas Sla2 and Ssb1/2 interact with both forms of Sup35 with similar efficiency.

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Section: Introductionmentioning

confidence: 99%

Variant-specific [PSI⁺] Infection Is Transmitted by Sup35 Polymers within [PSI⁺] Aggregates with Heterogeneous Protein Composition

Bagriantsev

Gracheva

Richmond

et al. 2008

MBoC

121

149

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“…Saccharomyces cerevisiae is a very convenient experimental model for studying the amyloid phenomenon, due to similarity of mechanisms of aggregate formation in higher organisms and in yeast and the fact that both mammals and yeast may contain self-propagating infectious amyloids, called prions. 4,5 In contrast to mammalian prions, which are responsible for incurable neurodegenerative diseases, yeast prions manifest themselves as heritable elements with unusual genetic properties. The increasing number of discovered yeast prions suggests that this phenomenon is widespread.…”

Section: Introductionmentioning

confidence: 99%

Interdependence of amyloid formation in yeast

Urakov

Vishnevskaya

Alexandrov

et al. 2010

Prion

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In eukaryotic cells amyloid aggregates may incorporate various functionally unrelated proteins. In mammalian diseases this may cause amyloid toxicity, while in yeast this could contribute to prion phenotypes. Insolubility of amyloids in the presence of strong ionic detergents, such as SDS or sarcosyl, allows discrimination between amorphous and amyloid aggregates. Here, we used this property of amyloids to study the interdependence of their formation in yeast. We observed that SDS-resistant polymers of proteins with extended polyglutamine domains caused the appearance of SDS or sarcosyl-insoluble polymers of three tested chromosomally-encoded Q/N-rich proteins, Sup35, Rnq1 and Pub1. These polymers were non-heritable, since they could not propagate in the absence of polyglutamine polymers. Sup35 prion polymers caused the appearance of non-heritable sarcosyl-resistant polymers of Pub1. Since eukaryotic genomes encode hundreds of proteins with long Q/N-rich regions, polymer interdependence suggests that conversion of a single protein into polymer form may significantly affect cell physiology by causing partial transfer of other Q/N-rich proteins into a non-functional polymer state.

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“…In conclusion the results of this study support the view that natural products, and in particular those derived from invertebrates, are a rich but until now untapped and therefore potentially important source of anti-prion compounds. Recent research findings have implicated prions (or at least prion-like mechanisms) in a number of chronic neurodegenerative disorders with high and increasing incidence including Alzheimer's disease [39] and Multiple systems atrophy [40]. Therefore, compounds such as those identified in this study (or compounds based on them) that would be predicted to cross the blood-brain barrier and deliver anti-prion activity to the brain are of potentially great significance.…”

Section: Discussionmentioning

confidence: 91%

Yeast-based screening of natural product extracts results in the identification of prion inhibitors from a marine sponge

Jennings

Ahmed

Munn

et al. 2018

Prion

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One of the major medical challenges of the twenty-first century is the treatment of incurable and fatal neurodegenerative disorders caused by misfolded prion proteins. Since the discovery of these diseases a number of studies have been conducted to identify small molecules for their treatment, however to date no curative treatment is available. These studies can be highly expensive and time consuming, but more recent experimental approaches indicate a significant application for yeast prions in these studies. We therefore used yeast prions to optimize previous high-throughput methods for the cheaper, easier and more rapid screening of natural extracts. Through this approach we aimed to identify natural yeast-prion inhibitors that could be useful in the development of novel treatment strategies for neurodegenerative disorders. We screened 500 marine invertebrate extracts from temperate waters in Australia allowing the identification of yeast-prion inhibiting extracts. Through the bioassay-driven chemical investigation of an active Suberites sponge extract, a group of bromotyrosine derivatives were identified as potent yeast-prion inhibitors. This study outlines the importance of natural products and yeast prions as a first-stage screen for the identification of new chemically diverse and bioactive compounds.

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Neurodegenerative amyloidoses: Yeast model

Cited by 10 publications

References 53 publications

Variant-specific [PSI⁺] Infection Is Transmitted by Sup35 Polymers within [PSI⁺] Aggregates with Heterogeneous Protein Composition

Variant-specific [PSI⁺] Infection Is Transmitted by Sup35 Polymers within [PSI⁺] Aggregates with Heterogeneous Protein Composition

Interdependence of amyloid formation in yeast

Yeast-based screening of natural product extracts results in the identification of prion inhibitors from a marine sponge

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Neurodegenerative amyloidoses: Yeast model

Cited by 10 publications

References 53 publications

Variant-specific [PSI+] Infection Is Transmitted by Sup35 Polymers within [PSI+] Aggregates with Heterogeneous Protein Composition

Variant-specific [PSI+] Infection Is Transmitted by Sup35 Polymers within [PSI+] Aggregates with Heterogeneous Protein Composition

Interdependence of amyloid formation in yeast

Yeast-based screening of natural product extracts results in the identification of prion inhibitors from a marine sponge

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Variant-specific [PSI⁺] Infection Is Transmitted by Sup35 Polymers within [PSI⁺] Aggregates with Heterogeneous Protein Composition

Variant-specific [PSI⁺] Infection Is Transmitted by Sup35 Polymers within [PSI⁺] Aggregates with Heterogeneous Protein Composition