Yeast Prions Compared to Functional Prions and Amyloids

Wickner, Reed B.; Edskes, Herman K.; Son, Moonil; Bezsonov, Evgeny E.; DeWilde, Morgan P; Ducatez, Mathieu

doi:10.1016/j.jmb.2018.04.022

Cited by 33 publications

(27 citation statements)

References 132 publications

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“…Various proteins and peptides with different amino acid sequences are amyloidogenic 58 . Yet, despite all of them being capable of forming amyloid fibrils in vivo, they display different biological activities [59][60][61] . Changing the primary sequence of an amyloidogenic protein, e.g., by point mutations also alters the energy landscape for that protein, resulting in structural polymorphism that could be responsible for variations in their biological or pathological activities.…”

Section: Discussionmentioning

confidence: 99%

Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

et al. 2020

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Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-distance curve-based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.

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Section: Discussionmentioning

confidence: 99%

Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

et al. 2020

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“…Yeast and bacteria express a hexameric, cytosolic AAA + ‐ATPase protein disaggregase that dissolves insoluble species and either refolds them with the assistance of other chaperones or delivers the solubilized species to cytosolic proteases . AAA + ‐ATPases couple ATP hydrolysis to drive energy‐expensive processes, such as the unwinding of DNA, remodeling of the lipid bilayer, protein transport, chromatin condensation, transcription regulation, prion severing, as well as protein disaggregation and degradation . In yeast, the disaggregase is known as Hsp104 .…”

Section: Introductionmentioning

confidence: 99%

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

et al. 2019

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Misfolded proteins in the endoplasmic reticulum (ER) are selected for ER-associated degradation (ERAD). More than 60 disease-associated proteins are substrates for the ERAD pathway due to the presence of missense or nonsense mutations. In yeast, the Hsp104 molecular chaperone disaggregates detergent-insoluble ERAD substrates, but the spectrum of diseaseassociated ERAD substrates that may be aggregation prone is unknown. To determine if Hsp104 recognizes aggregation-prone ERAD substrates associated with human diseases, we developed yeast expression systems for a hydrophobic lipid-binding protein, apolipoprotein B (ApoB), along with a chimeric protein harboring a nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator (CFTR) into which disease-causing mutations were introduced. We discovered that Hsp104 facilitates the degradation of ER-associated ApoB as well as a truncated CFTR chimera in which a premature stop codon corresponds to a disease-causing mutation. Chimeras containing a wild-type version of the CFTR domain or a different mutation were stable and thus Hsp104 independent. We also discovered that the detergent solubility of the unstable chimera was lower than the stable chimeras, and Hsp104 helped retrotranslocate the unstable chimera from the ER, consistent with disaggregase activity. To determine why the truncated chimera was unstable, we next performed molecular dynamics simulations and noted significant unraveling of the CFTR nucleotide-binding domain. Because human cells lack Hsp104, Additional Supporting Information may be found in the online version of this article.Lynley M. Doonan, Christopher J. Guerriero, and G. Michael Preston contributed equally to this work.Significance statement: Misfolded proteins can aggregate, which impairs cellular homeostasis and can give rise to disease. Although yeast express an enzyme that dissolves aggregates, humans lack this protein. We show that human aggregation-prone proteins associated with the endoplasmic reticulum are substrates for the yeast disaggregase. These data suggest that a human analog of the yeast disaggregase exists or that another mechanism removes aggregates associated with the endoplasmic reticulum.these data indicate that an alternate disaggregase or mechanism facilitates the removal of aggregation-prone, disease-causing ERAD substrates in their native environments.

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“…There, a normal protein (PrP C ) conformationally changes into a malicious and infectious PrP Sc prion protein [ 211 ]. Besides these disease-causing prions, a plethora of prions with mostly unknown function has been discovered also in yeast [ 212 , 213 ]. Except for Podospora anserina ’s [Het-s] prion, most functions of all these prions are unclear and all are toxic, or at least growth-inhibitory, but still are supposed to be beneficial for the survival of cells under stress conditions [ 214 , 215 , 216 ].…”

Section: Studying Prion Characteristics Of Aβ and Tau In Yeastmentioning

confidence: 99%

Recent Insights on Alzheimer’s Disease Originating from Yeast Models

Seynnaeve

Vecchio

Fruhmann

et al. 2018

IJMS

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In this review article, yeast model-based research advances regarding the role of Amyloid-β (Aβ), Tau and frameshift Ubiquitin UBB+1 in Alzheimer’s disease (AD) are discussed. Despite having limitations with regard to intercellular and cognitive AD aspects, these models have clearly shown their added value as complementary models for the study of the molecular aspects of these proteins, including their interplay with AD-related cellular processes such as mitochondrial dysfunction and altered proteostasis. Moreover, these yeast models have also shown their importance in translational research, e.g., in compound screenings and for AD diagnostics development. In addition to well-established Saccharomyces cerevisiae models, new upcoming Schizosaccharomyces pombe, Candida glabrata and Kluyveromyces lactis yeast models for Aβ and Tau are briefly described. Finally, traditional and more innovative research methodologies, e.g., for studying protein oligomerization/aggregation, are highlighted.

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Yeast Prions Compared to Functional Prions and Amyloids

Cited by 33 publications

References 132 publications

Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

Recent Insights on Alzheimer’s Disease Originating from Yeast Models

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