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Modeling in yeast the neurotoxicity and neurodegeneration induced by manganese


Manganese (Mn) is an essential trace mineral that can be (neuro)toxic, especially during developmental stages due to unclear mechanisms suggesting the need for additional and improved studies. We employ adverse outcome pathways (AOPs); a novel tool designed to provide a clear-cut mechanistic representation of critical toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event (MIE), a series of intermediate steps and key events, and an adverse outcome (AO). These AOs can be revealed by systems biology, which is an integrative discipline that seeks to explain the properties and behaviour of complex biological systems in terms of their components and their interactions. Recently, using toxicogenomic approaches our group have discovered that Mn can disrupt several pathways, which appear be common among cross-species; where, disruption of protein synthesis might be a key mechanism for Mn- induced neurotoxicity and neurodegeneration. Therefore, we propose to further investigate the influence of Mn on the regulation of translation. In this way, we can have a better understanding of not only a primary molecular mechanism of Mn toxicity, but also its effect in neurodegeneration in higher mammals. The present project aims to study protein synthesis under Mn-induced stress in the yeast model, and evaluate its potential extrapolation for other biological levels and their implication for neurotoxicity and neurodegeneration induced by the Mn. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HERNANDEZ, RAUL BONNE; CARRASCAL, MONTSERRAT; ABIAN, JOAQUIN; MICHALKE, BERNHARD; FARINA, MARCELO; GONZALEZ, YASMILDE RODRIGUEZ; IYIRHIARO, GRACE O.; MOTESHAREIE, HOUMAN; BURNSIDE, DANIEL; GOLSHANI, ASHKAN; et al. Manganese-induced neurotoxicity in cerebellar granule neurons due to perturbation of cell network pathways with potential implications for neurodegenerative disorders. METALLOMICS, v. 12, n. 11, p. 1656-1678, . (16/50483-6, 15/24207-9, 16/00371-7, 14/08990-2)
HERNANDEZ, RAUL BONNE; MOTESHAREIE, HOUMAN; BURNSIDE, DANIEL; MCKAY, BRUCE; GOLSHANI, ASHKAN. Manganese-induced cellular disturbance in the baker's yeast, Saccharomyces cerevisiae with putative implications in neuronal dysfunction. SCIENTIFIC REPORTS, v. 9, . (16/00371-7, 16/50483-6)
HERNANDEZ, RAUL BONNE; DE SOUZA-PINTO, NADJA C.; KLEINJANS, JOS; VAN HERWIJNEN, MARCEL; PIEPERS, JOLANDA; MOTESHAREIE, HOUMAN; BURNSIDE, DANIEL; GOLSHANI, ASHKAN. Manganese-Induced Neurotoxicity through Impairment of Cross-Talk Pathways in Human Neuroblastoma Cell Line SH-SY5Y Differentiated with Retinoic Acid. TOXICS, v. 9, n. 12, . (15/24207-9, 19/27840-5, 16/50483-6)

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