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Hernández, R.B.* ; Carrascal, M.* ; Abian, J.* ; Michalke, B. ; Farina, M.* ; Gonzalez, Y.R.* ; Iyirhiaro, G.O.* ; Moteshareie, H.* ; Burnside, D.* ; Golshani, A.* ; Suñol, C.*

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

Metallomics 12, 1656-1678 (2020)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 ∼ 7-9 μM), which was higher than that of MnCl2 (LC50 ∼ 27 μM). 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 μM), 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ethylene-bis-dithiocarbamate; Oxidative-phosphorylation; Proteasome Inhibition; Endoplasmic-reticulum; Chemical Speciation; Signaling Pathways; Proteomic Analysis; Protein-synthesis; Dopamine Neurons; Golgi-apparatus
ISSN (print) / ISBN 1756-5901
e-ISSN 1756-591X
Journal Metallomics
Quellenangaben Volume: 12, Issue: 11, Pages: 1656-1678 Article Number: , Supplement: ,
Publisher Royal Society of Chemistry (RSC)
Publishing Place Thomas Graham House, Science Park, Milton Rd, Cambridge Cb4 0wf, Cambs, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit BioGeoChemistry and Analytics (BGC)
Grants Spanish Ministry of Health
CNPq
FAPESP