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Nevertheless, chronic and\/or acute exposure to this metal, especially during early life stages, can lead to neurotoxicity and dementia by unclear mechanisms. Thus, based on previous works of our group with yeast and zebrafish, we hypothesized that the mechanisms mediating manganese-induced neurotoxicity can be associated with the alteration of protein metabolism. These mechanisms may also depend on the chemical speciation of manganese. Therefore, the current study aimed at investigating the mechanisms mediating the toxic effects of manganese in primary cultures of cerebellar granule neurons (CGNs). By exposing cultured CGNs to different chemical species of manganese ([[2-[(dithiocarboxy)amino]ethyl]carbamodithioato]](2-)-kS,kS\u2032]manganese, named maneb (MB), and [[1,2-ethanediylbis[carbamodithioato]](2-)]manganese mixture with [[1,2-ethanediylbis[carbamodithioato]](2-)]zinc, named mancozeb (MZ), and manganese chloride (MnCl2)), and using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, we observed that both MB and MZ induced similar cytotoxicity (LC50 \u223c 7\u20139 \u03bcM), which was higher than that of MnCl2 (LC50 \u223c 27 \u03bcM). Subsequently, we applied systems biology approaches, including metallomics, proteomics, gene expression and bioinformatics, and revealed that independent of chemical speciation, for non-cytotoxic concentrations (0.3\u20133 \u03bcM), Mn-induced neurotoxicity in CGNs is associated with metal dyshomeostasis and impaired protein metabolism. In this way, we verified that MB induced more post-translational alterations than MnCl2, which can be a plausible explanation for cytotoxic differences between both chemical species. The metabolism of proteins is one of the most energy consuming cellular processes and its impairment appears to be a key event of some cellular stress processes reported separately in other studies such as cell cycle arrest, energy impairment, cell signaling, excitotoxicity, immune response, potential protein accumulation and apoptosis. Interestingly, we verified that Mn-induced neurotoxicity shares pathways associated with the development of Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, and Parkinson's disease. This has been observed in baker's yeast and zebrafish suggesting that the mode of action of Mn may be evolutionarily conserved.<\/jats:p>","DOI":"10.1039\/d0mt00085j","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T11:20:17Z","timestamp":1595330417000},"page":"1656-1678","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Manganese-induced neurotoxicity in cerebellar granule neurons due to perturbation of cell network pathways with potential implications for neurodegenerative disorders"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3768-4157","authenticated-orcid":false,"given":"Ra\u00fal Bonne","family":"Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Laboratory of Bioinorganic and Environmental Toxicology \u2013 LABITA, Department of Exact and Earth Sciences, Federal University of S\u00e3o Paulo , Rua Prof. Artur Riedel, 275, CEP 09972-270, Diadema, SP,","place":["Brazil"]},{"name":"Department of Biology, Carleton University , 209 Nesbitt Biology Building, 1125 Colonel by Drive, Ottawa, K1S 5B6, ON,","place":["Canada"]},{"name":"Department of Neurochemistry and Neuropharmacology, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona, IIBB-CSIC, IDIBAPS, CIBERESP , Barcelona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Carrascal","sequence":"additional","affiliation":[{"name":"CSIC\/UAB Proteomics Laboratory, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona, IIBB-CSIC, IDIBAPS , Barcelona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin","family":"Abian","sequence":"additional","affiliation":[{"name":"CSIC\/UAB Proteomics Laboratory, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona, IIBB-CSIC, IDIBAPS , Barcelona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Michalke","sequence":"additional","affiliation":[{"name":"Helmholtz Zentrum M\u00fcnchen GmbH, German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry , Ingolst\u00e4dter Landstr. 1, 85764 Neuherberg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Farina","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Centro de Ci\u00eancias Biol\u00f3gicas, Campus Universit\u00e1rio, Trindade, Bloco C. Universidade Federal de Santa Catarina , Florian\u00f3polis, Santa Catarina, CEP 88040-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmilde Rodriguez","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , 451 Smyth Road, Ottawa, ON, K1H 8M5,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace O","family":"Iyirhiaro","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , 451 Smyth Road, Ottawa, ON, K1H 8M5,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houman","family":"Moteshareie","sequence":"additional","affiliation":[{"name":"Department of Biology, Carleton University , 209 Nesbitt Biology Building, 1125 Colonel by Drive, Ottawa, K1S 5B6, ON,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Burnside","sequence":"additional","affiliation":[{"name":"Department of Biology, Carleton University , 209 Nesbitt Biology Building, 1125 Colonel by Drive, Ottawa, K1S 5B6, ON,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashkan","family":"Golshani","sequence":"additional","affiliation":[{"name":"Department of Biology, Carleton University , 209 Nesbitt Biology Building, 1125 Colonel by Drive, Ottawa, K1S 5B6, ON,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9367-8483","authenticated-orcid":false,"given":"Cristina","family":"Su\u00f1ol","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry and Neuropharmacology, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona, IIBB-CSIC, IDIBAPS, CIBERESP , Barcelona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,7]]},"reference":[{"key":"2026041420234111700_cit1","volume-title":"Manganese and Its Compounds: Environmental Aspect","author":"Howe","year":"2004"},{"key":"2026041420234111700_cit2","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1039\/b822579f","article-title":"Distribution and behavior of manganese in the Alto do Paranapanema Basin","volume":"11","author":"Bonne Hern\u00e1ndez","year":"2009","journal-title":"J. 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