Manganese-induced neurotoxicity in cerebellar granule neurons due to perturbation of cell network pathways with potential implications for neurodegenerative disorders

Autor(es):Mostrar menos -

Hernandez, Raul Bonne ^{[1, 2, 3]} ; Carrascal, Montserrat ^[4] ; Abian, Joaquin ^[4] ; Michalke, Bernhard ^[5] ; Farina, Marcelo ^[6] ; Gonzalez, Yasmilde Rodriguez ^[7] ; Iyirhiaro, Grace O. ^[7] ; Moteshareie, Houman ^[2] ; Burnside, Daniel ^[2] ; Golshani, Ashkan ^[2] ; Sunol, Cristina ^[3]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Exact & Earth Sci, Lab Bioinorgan & Environm Toxicol LABITA, Rua Prof Artur Riedel 275, BR-09972270 Diadema, SP - Brazil

^[2] Carleton Univ, Dept Biol, 209 Nesbitt Biol Bldg, 1125 Colonel Dr, Ottawa, ON K1S 5B6 - Canada

^[3] IDIBAPS, IIBB CSIC, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, Barcelona - Spain

^[4] IDIBAPS, IIBB CSIC, Inst Invest Biomed Barcelona, CSIC UAB Prote Lab, Barcelona - Spain

^[5] Helmholtz Zentrum Munchen GmbH, German Res Ctr Environm Hlth, Res Unit Analyt BioGeoChem, Ingolstadter Landstr 1, D-85764 Neuherberg - Germany

^[6] Campus Univ Trindade, Ctr Ciencias Biol, Dept Bioquim, Campus Univ, Bloco C Univ Fed Santa Catarina, BR-88040900 Florianopolis, SC - Brazil

^[7] Univ Ottawa, Fac Med, Dept Cellular & Mol Med, 451 Smyth Rd, Ottawa, ON K1H 8M5 - Canada

• Tipo de documento: Artigo Científico
• Fonte: METALLOMICS; v. 12, n. 11, p. 1656-1678, NOV 1 2020.
• Citações Web of Science: 0

Resumo

Manganese (Mn) is essential for living organisms, playing an important role in nervous system function. 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 `]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 similar to 7-9 mu M), which was higher than that of MnCl2 (LC50 similar to 27 mu M). Subsequently, we applied systems biology approaches, including metallomics, proteomics, gene expression and bioinformatics, and revealed that independent of chemical speciation, for non-cytotoxic concentrations (0.3-3 mu M), 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. (AU)

• Processo FAPESP: 16/50483-6 - Modeling in yeast the neurotoxicity and neurodegeneration induced by manganese
• Beneficiário: Raúl Bonne Hernández
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/24207-9 - Desenvolvimento e aplicação de um quadro de via de resultado adverso para compreender e prever a neurotoxicidade do desenvolvimento e neurodegeneração induzida pelo manganês
• Beneficiário: Raúl Bonne Hernández
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/00371-7 - Estudos de toxicogenômica entre espécies para o desenvolvimento de um quadro de via de resultado adverso para compreender e prever tanto neurotoxicidade durante o desenvolvimento como a neurodegeneração induzida pelo manganês
• Beneficiário: Raúl Bonne Hernández
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 14/08990-2 - Estudos de proteômica e metalômica para a compreensão da neurotoxicidade induzida por pesticidas que contém manganês durante desenvolvimento
• Beneficiário: Raúl Bonne Hernández
• Modalidade de apoio: Bolsas no Exterior - Pesquisa