SPELL - S. cerevisiae

Citation	Chen X, Bisschops MMM, Agarwal NR, Ji B, Shanmugavel KP, Petranovic D . Interplay of Energetics and ER Stress Exacerbates Alzheimer's Amyloid-_ (A_) Toxicity in Yeast. Front Mol Neurosci, 2017.
PubMed ID	28798664
Short Description	Expression data from Saccharomyces cerevisiae
# of Conditions	24
Full Description	Alzheimers disease (AD) is a progressive neurodegenerative disorder. Oligomers of Amyloid-_ peptides (A_) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of A_ associated with AD are A_40 and A_42, the latter being more prone to form oligomers and toxic. Humanized yeast models are currently applied to unravel the cellular mechanisms behind A_ toxicity. Here, we took a systems biology approach to study two yeast AD models which expressed either A_40 or A_42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected the chronological lifespan and reduced confounding effects of variations during cell growth. Reduced growth rates and biomass yields were observed upon expression of A_42, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in A_42 expressing cells, which matched with observed aberrant fragmented mitochondrial structures. Genome-wide expression levels analysis showed that A_42 expression triggers strong ER stress and unfolded protein responses (UPR). Expression of A_40 induced only mild ER stress, leading to activation of UPR target genes that cope with misfolded proteins, which resulted in hardly affected physiology. The combination of well-controlled cultures and AD yeast models strengthen our understanding of how cells translate different levels of A_ toxicity signals into particular cell fate programs, and further enhance their role as a discovery platform to identify potential therapies.
Tags	disease