Manganese-Induced Neurotoxicity through Impairment of Cross-Talk Pathways in Human Neuroblastoma Cell Line SH-SY5Y Differentiated with Retinoic Acid
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Updated: Oct 9, 2025
Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line
Published on: February 17, 2016
Raúl Bonne Hernández1,2, Nadja C de Souza-Pinto3, Jos Kleinjans4
1Laboratory of Bioinorganic and Environmental Toxicology-LABITA, Department of Chemistry, Federal University of São Paulo, Rua Prof. Artur Riedel, 275, Diadema 09972-270, SP, Brazil.
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.
Insights
Manganese (Mn) exposure causes neurotoxicity by disrupting protein metabolism. MnCl2 affects amino acid and protein synthesis, while Citrate of Mn(II) impairs protein degradation, both impacting pathways common in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Manganese (Mn) exposure is linked to neurotoxicity and neurodegenerative diseases like Parkinson's.
- The precise mechanisms underlying Mn-induced neurotoxicity remain largely unknown.
- Understanding these mechanisms is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the differential effects of two manganese chemical species on human neuroblastoma cells.
- To elucidate the molecular pathways involved in manganese-induced neurotoxicity.
- To compare Mn-induced cellular responses with pathways implicated in neurodegenerative diseases.
Main Methods:
- Exposure of RA-differentiated SH-SY5Y human neuroblastoma cells to MnCl2 and Citrate of Mn(II).
- Cell viability assays to assess toxicity.
- Transcriptomics and bioinformatics analyses to identify affected molecular pathways.
Main Results:
- Both MnCl2 and Citrate of Mn(II) induced significant cytotoxicity in RA-SH-SY5Y cells.
- MnCl2 disrupted amino acid metabolism, impacting RNA metabolism and protein synthesis.
- Citrate of Mn(II) inhibited the E3 ubiquitin ligases-mediated protein degradation pathway.
- Mn(II)-induced cytotoxicity shared 84% of pathways with known neurodegenerative diseases.
Conclusions:
- Manganese-induced neurotoxicity involves disruption of protein metabolism, with distinct effects from different chemical species.
- The findings highlight the role of protein metabolism dysregulation, including synthesis and degradation, in Mn neurotoxicity.
- The study identifies a significant overlap between Mn-induced cellular pathways and those in neurodegenerative diseases, suggesting potential mechanisms.
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