Development of a Novel Yeast Cell-Based System for Studying the Aggregation of Alzheimer’s Disease-Associated Aβ Peptides in vivo

Haar, Tobias von der; Jossé, Lyne; Wright, Paul D.; Zenthon, Jo; Tuite, Mick F.

doi:10.1159/000101838

Cited by 42 publications

(32 citation statements)

References 97 publications

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“…Interestingly, a fusion protein of Sup35 and Aβ immediately aggregates in yeast cells and the resulting chimeric prion replicates independent of the presence of Hsp104. 47 These findings indicate that the mechanism of action by Hsp104 is highly dependent on the aggregation propensity of the substrate and differs among amyloid-forming proteins.…”

Section: Binding Of Aβ Can Be Monitored By Atp Turnover Of Hsp104 Andmentioning

confidence: 94%

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Arimon

Grimminger

Sanz

et al. 2008

Journal of Molecular Biology

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The heat shock protein Hsp104 has been reported to possess the ability to modulate protein aggregation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates, including amyloid fibrils, in yeast, Escherichia coli, mammalian cell cultures, and animal models of Huntington's disease and Parkinson's disease. To provide mechanistic insight into the molecular mechanisms by which Hsp104 modulates aggregation and fibrillogenesis, the effect of Hsp104 on the fibrillogenesis of amyloid beta (Aβ) was investigated by characterizing its ability to interfere with oligomerization and fibrillogenesis of different species along the amyloid-formation pathway of Aβ. To probe the disaggregation activity of Hsp104, its ability to dissociate preformed protofibrillar and fibrillar aggregates of Aβ was assessed in the presence and in the absence of ATP. Our results show that Hsp104 inhibits the fibrillization of monomeric and protofibrillar forms of Aβ in a concentration-dependent but ATP-independent manner. Inhibition of Aβ fibrillization by Hsp104 is observable up to Hsp104/Aβ stoichiometric ratios of 1:1000, suggesting a preferential interaction of Hsp104 with aggregation intermediates (e.g., oligomers, protofibrils, small fibrils) on the pathway of Aβ amyloid formation. This hypothesis is consistent with our observations that Hsp104 (i) interacts with Aβ protofibrils, (ii) inhibits conversion of protofibrils into amyloid fibrils, (iii) arrests fibril elongation and reassembly, and (iv) abolishes the capacity of protofibrils and sonicated fibrils to seed the fibrillization of monomeric Aβ. Together, these findings suggest that the strong inhibition of Aβ fibrillization by Hsp104 is mediated by its ability to act at different stages and target multiple intermediates on the pathway to amyloid formation.

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Section: Binding Of Aβ Can Be Monitored By Atp Turnover Of Hsp104 Andmentioning

confidence: 94%

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Arimon

Grimminger

Sanz

et al. 2008

Journal of Molecular Biology

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“…Five ODs of cells were lysed in 100 µl standard buffer without urea for blots with anti-eRF1 antibodies (MT44), or in buffer containing urea for blots with anti-eRF3 antibodies (MT30). Antibodies were raised in rabbit and have been described before (30,31). …”

Section: Methodsmentioning

confidence: 99%

Decoding accuracy in eRF1 mutants and its correlation with pleiotropic quantitative traits in yeast

Merritt

Naemi

Mugnier

et al. 2010

Nucleic Acids Research

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Translation termination in eukaryotes typically requires the decoding of one of three stop codons UAA, UAG or UGA by the eukaryotic release factor eRF1. The molecular mechanisms that allow eRF1 to decode either A or G in the second nucleotide, but to exclude UGG as a stop codon, are currently not well understood. Several models of stop codon recognition have been developed on the basis of evidence from mutagenesis studies, as well as studies on the evolutionary sequence conservation of eRF1. We show here that point mutants of Saccharomyces cerevisiae eRF1 display significant variability in their stop codon read-through phenotypes depending on the background genotype of the strain used, and that evolutionary conservation of amino acids in eRF1 is only a poor indicator of the functional importance of individual residues in translation termination. We further show that many phenotypes associated with eRF1 mutants are quantitatively unlinked with translation termination defects, suggesting that the evolutionary history of eRF1 was shaped by a complex set of molecular functions in addition to translation termination. We reassess current models of stop-codon recognition by eRF1 in the light of these new data.

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“…Over the past two decades, several humanized yeast models have been developed to study Aβ toxicity (Fruhmann et al, 2017). The earlier models have been successfully used to monitor aggregation patterns of Aβ (Bagriantsev and Liebman, 2006; von der Haar et al, 2007), but failed to recapitulate its toxic effects. More recently developed models illustrated the importance of intracellular trafficking for Aβ toxicity (Treusch et al, 2011; D'Angelo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Interplay of Energetics and ER Stress Exacerbates Alzheimer's Amyloid-β (Aβ) Toxicity in Yeast

Chen

Bisschops

Agarwal

et al. 2017

Front. Mol. Neurosci.

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Alzheimer's disease (AD) is a progressive neurodegeneration. Oligomers of amyloid-β peptides (Aβ) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of Aβ associated with AD are Aβ40 and Aβ42, the latter being more toxic and prone to form oligomers. Here, we took a systems biology approach to study two humanized yeast AD models which expressed either Aβ40 or Aβ42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected chronological lifespan and reduced variations during cell growth. Reduced growth rates and biomass yields were observed upon Aβ42 expression, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in Aβ42 expressing cells, which matched with observed aberrant mitochondrial structures. Genome-wide expression level analysis showed that Aβ42 expression triggered strong ER stress and unfolded protein responses. Equivalent expression of Aβ40, however, induced only mild ER stress, which resulted in hardly affected physiology. Using AD yeast models in well-controlled cultures strengthened our understanding on how cells translate different Aβ toxicity signals into particular cell fate programs, and further enhance their potential as a discovery platform to identify possible therapies.

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Development of a Novel Yeast Cell-Based System for Studying the Aggregation of Alzheimer’s Disease-Associated Aβ Peptides in vivo

Cited by 42 publications

References 97 publications

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Decoding accuracy in eRF1 mutants and its correlation with pleiotropic quantitative traits in yeast

Interplay of Energetics and ER Stress Exacerbates Alzheimer's Amyloid-β (Aβ) Toxicity in Yeast

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