Abstract
Manganese (Mn) is an important element; yet acute and/or chronic exposure to this metal has been linked to neurotoxicity and neurodegenerative illnesses such as Parkinson’s disease and others via an unknown mechanism. To better understand it, we exposed a human neuroblastoma cell model (SH-SY5Y) to two Mn chemical species, MnCl2 and Citrate of Mn(II) (0–2000 µM), followed by a cell viability assay, transcriptomics, and bioinformatics. Even though these cells have been chemically and genetically modified, which may limit the significance of our findings, we discovered that by using RA-differentiated cells instead of undifferentiated SH-SY5Y cell line, both chemical species induce a similar toxicity, potentially governed by disruption of protein metabolism, with some differences. The MnCl2 altered amino acid metabolism, which affects RNA metabolism and protein synthesis. Citrate of Mn(II), however, inhibited the E3 ubiquitin ligases–target protein degradation pathway, which can lead to the buildup of damaged/unfolded proteins, consistent with histone modification. Finally, we discovered that Mn(II)-induced cytotoxicity in RA-SH-SY5Y cells shared 84 percent of the pathways involved in neurodegenerative diseases.
Highlights
FDRPeptide chain elongationViral mRNA TranslationSRP-dependent cotranslational protein targeting to membraneEukaryotic Translation TerminationNonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)Formation of a pool of free 40S subunitsL13a-mediated translational silencing of Ceruloplasmin expressionGTP hydrolysis and joining of the 60S ribosomal subunit RibosomeNonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
We revealed that retinoic acid (RA)-differentiated SH-SY5Y
Cells respond differently to distinct chemical species of Mn, which was not considered in previous studies with NoRA-differentiated SH-SY5Y cells
Summary
FDRPeptide chain elongationViral mRNA TranslationSRP-dependent cotranslational protein targeting to membraneEukaryotic Translation TerminationNonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)Formation of a pool of free 40S subunitsL13a-mediated translational silencing of Ceruloplasmin expressionGTP hydrolysis and joining of the 60S ribosomal subunit RibosomeNonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC). Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC). Formation of a pool of free 40S subunits. GTP hydrolysis and joining of the 60S ribosomal subunit Ribosome. Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
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