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Manganese-induced cellular disturbance in the baker''s yeast, Saccharomyces cerevisiae with putative implications in neuronal dysfunction.
Hernández RB
,
Moteshareie H
,
Burnside D
,
McKay B
,
Golshani A
.
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Manganese (Mn) is an essential element, but in humans, chronic and/or acute exposure to this metal can lead to neurotoxicity and neurodegenerative disorders including Parkinsonism and Parkinson''s Disease by unclear mechanisms. To better understand the effects that exposure to Mn2+ exert on eukaryotic cell biology, we exposed a non-essential deletion library of the yeast Saccharomyces cerevisiae to a sub-inhibitory concentration of Mn2+ followed by targeted functional analyses of the positive hits. This screen produced a set of 43 sensitive deletion mutants that were enriched for genes associated with protein biosynthesis. Our follow-up investigations demonstrated that Mn reduced total rRNA levels in a dose-dependent manner and decreased expression of a β-galactosidase reporter gene. This was subsequently supported by analysis of ribosome profiles that suggested Mn-induced toxicity was associated with a reduction in formation of active ribosomes on the mRNAs. Altogether, these findings contribute to the current understanding of the mechanism of Mn-triggered cytotoxicity. Lastly, using the Comparative Toxicogenomic Database, we revealed that Mn shared certain similarities in toxicological mechanisms with neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer''s, Parkinson''s and Huntington''s diseases.
Discovery Grant 2013-2018 Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)
Figure 2. The inferred and enriched PPI network from 43 genes that sensitize yeast to Mn when deleted. Analysis performed using the String database. Network properties are as follows: The minimum required interaction score, to be included at the predicted network, was accepted with a threshold on the high confidence equal 0.7; Number of nodes: 143; Number of edges: 594; Expected number of edges: 287; Average (avg) node degree: 8.31; avg. local clustering coefficient: 0.652; PPI enrichment p-value: <1.0e-16. Nodes and edges represent proteins and PPIs, respectively. Red nodes (protein processing in endoplasmic reticulum); blue nodes (metabolic pathways); dark green nodes (N-Glycan biosynthesis); cyan nodes (cell cycle); yellow nodes (ubiquitin-mediated proteolysis); orange nodes (meiosis); maroon nodes (DNA replication); purple nodes (amino acid biosynthesis); magenta nodes (arginine and proline metabolism); lime green nodes (alanine, aspartate and glutamate metabolism). The protein with black points in the center represent the MAPK signaling pathway. Proteins that are not connected to at least one partner are not shown.
Figure 5. Mn-induced disruption pathways in yeast (A) share similarities with certain pathways linked to neurotoxicity and neurodegeneration (B). Analysis performed with the Comparative Toxicogenomic Databasewhich containscurated data regarding the mechanisms of action for neurodegenetative disorders. The results these analyses indicate overlapping pathways related to Mn Toxicity, AD (Alzheimer’s Disease), Amyotrophic Lateral Sclerosis (ALS), HD (Huntington’s Disease), and PD (Parkinson’s Disease).
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