Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Fruhmann, Gernot; Seynnaeve, David; Zheng, Jie; Ven, Karen; Molenberghs, Sofie; Wilms, Tobias; Liu, Beidong; Winderickx, Joris; Franssens, Vanessa

doi:10.1016/j.mad.2016.05.002

Cited by 34 publications

(28 citation statements)

References 260 publications

(261 reference statements)

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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.…”

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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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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“…Interestingly, increasing evidence supports the notion that human GAPDH interacts with neurodegenerative disease‐related proteins, like α‐synuclein, by promoting the accumulation of oligomers and toxic aggregates (Ávila et al , ; Mikhaylova et al , ). The usefulness of S. cerevisiae as a model for the expression of human α‐synuclein showed by recent studies (Menezes et al , ; Fruhmann et al , ; Verbandt et al , ) provide an interesting system to check whether Tdh1,2‐Tdh3 binding plays a role in the aggregation of this protein and the possibility of using yeast for the study of the mechanisms that underlie in the propagation of neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

The formation of hybrid complexes between isoenzymes of glyceraldehyde‐3‐phosphate dehydrogenase regulates its aggregation state, the glycolytic activity and sphingolipid status in Saccharomyces cerevisiae

Rández-Gil

Sánchez-Adriá

Estruch

et al. 2019

Microbial Biotechnology

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Summary The glycolytic enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) has been traditionally considered a housekeeping protein involved in energy generation. However, evidence indicates that GAPDHs from different origins are tightly regulated and that this regulation may be on the basis of glycolysis‐related and glycolysis‐unrelated functions. In Saccharomyces cerevisiae, Tdh3 is the main GAPDH, although two other isoenzymes encoded by TDH1 and TDH2 have been identified. Like other GAPDHs, Tdh3 exists predominantly as a tetramer, although dimeric and monomeric forms have also been isolated. Mechanisms of Tdh3 regulation may thus imply changes in its oligomeric state or be based in its ability to interact with Tdh1 and/or Tdh2 to form hybrid complexes. However, no direct evidence of the existence of these interactions has been provided and the exact function of Tdh1,2 is unknown. Here, we show that Tdh1,2 immunopurified with a GFP‐tagged version of Tdh3 and that lack of this interaction stimulates the Tdh3’s aggregation. Furthermore, we found that the combined knockout of TDH1 and TDH2 promotes the loss of cell’s viability and increases the growing rate, glucose consumption and CO2 production, suggesting a higher glycolytic flux in the mutant cells. Consistent with this, the tdh3 strain, which displays impaired in vitro GAPDH activity, exhibited the opposite phenotypes. Quite remarkably, tdh1 tdh2 mutant cells show increased sensitivity to aureobasidin A, an inhibitor of the inositolphosphoryl ceramide synthase, while cells lacking Tdh3 showed improved tolerance. The results are in agreement with a link between glycolysis and sphingolipid (SLs) metabolism. Engineering Tdh activity could be thus exploited to alter the SLs status with consequences in different aspects of yeast biotechnology.

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“…Moreover, many findings in yeast models were confirmed in higher model systems, such as mammalian cell lines, C. elegans , mice and even human patients. The insights gained from the studies in yeast have contributed greatly to our understanding of the pathogenesis of HD (Winderickx et al, 2008 ; Khurana and Lindquist, 2010 ; Mason and Giorgini, 2011 ; Fruhmann et al, 2017 ). As most mediators and pathways of energy metabolism are highly conserved in eukaryotes, it is not surprising to see that mHTT fragment induces oxidative stress in yeast.…”

Section: Yeast Models Provide Insights Into Oxidative Stress In Hdmentioning

confidence: 99%

A Mitochondria-Associated Oxidative Stress Perspective on Huntington’s Disease

Zheng

Winderickx

Franssens

et al. 2018

Front. Mol. Neurosci.

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Huntington’s disease (HD) is genetically caused by mutation of the Huntingtin (HTT) gene. At present, the mechanisms underlying the defect of HTT and the development of HD remain largely unclear. However, increasing evidence shows the presence of enhanced oxidative stress in HD patients. In this review article, we focus on the role of oxidative stress in the pathogenesis of HD and discuss mediators and potential mechanisms involved in mutant HTT-mediated oxidative stress generation and progression. Furthermore, we emphasize the role of the unicellular organism Saccharomyces cerevisiae in investigating mutant HTT-induced oxidative stress. Overall, this review article provides an overview of the latest findings regarding oxidative stress in HD and potential therapeutic targets for HD.

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Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Cited by 34 publications

References 260 publications

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

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

The formation of hybrid complexes between isoenzymes of glyceraldehyde‐3‐phosphate dehydrogenase regulates its aggregation state, the glycolytic activity and sphingolipid status in Saccharomyces cerevisiae

A Mitochondria-Associated Oxidative Stress Perspective on Huntington’s Disease

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