Manganese increases Aβ and Tau protein levels through proteasome 20S and heat shock proteins 90 and 70 alteration, leading to SN56 cholinergic cell death following single and repeated treatment

Moyano, Paula; García, José M.; Anadón, M.J.; Naval, María Victoria; Frejo, María Teresa; Sola, Emma; Pelayo, Adela; Pino, Javier del

doi:10.1016/j.ecoenv.2020.110975

Cited by 17 publications

(30 citation statements)

References 106 publications

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“…A significant progress was achieved in the studies of the interplay between Mn and Nrf2, being the key transcriptional regulator of antioxidant system and redox homeostasis ( Figure 2 C). It has been found that Mn exposure (1 μM–200 μM for 24 h or two weeks) down-regulates Nrf2 signaling through alteration of Keap1 expression altogether resulting in reduced expression of antioxidant enzymes and heat shock proteins [ 98 ]. However, the effect of Mn on the Keap1–Nrf2–ARE signaling pathway was found to be biphasic.…”

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

“…Specifically, Mn-induced sirtuin down-regulation [ 98 ] results in increased acetylation of FOXO3a and PGC1α. Increased PGC1a acetylation is associated with reduced Nrf2 expression and down-regulation of Nrf2 target genes including γ-glutamylcysteine synthetase (γ-GCS), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H Quinone Dehydrogenase 1 (NQO-1), heme oxygenase 1 (HO-1) [ 98 ]. Mn exposure may also affect Nrf2 signaling through alterations of Keap1 expression [ 98 ].…”

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

“…Increased PGC1a acetylation is associated with reduced Nrf2 expression and down-regulation of Nrf2 target genes including γ-glutamylcysteine synthetase (γ-GCS), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H Quinone Dehydrogenase 1 (NQO-1), heme oxygenase 1 (HO-1) [ 98 ]. Mn exposure may also affect Nrf2 signaling through alterations of Keap1 expression [ 98 ]. In turn, increased FOXO3a acetylation results in decreased SOD and catalase expression that are up-regulated by deacetylated form, as well as promotes proapoptotic signaling through Bim and PUMA [ 103 ].…”

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

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Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

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Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

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Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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“…Mn induced Aβ plaque formation and increased Aβ mRNA levels, as well as Aβ protein levels, by increasing β-secretase (BACE) and γ-secretase cleavage activities in the cerebral cortex and hippocampus of an AD mouse model, particularly in the microglia [178], suggesting that Mn-induced microglial inflammation likely contributes to amyloidogenesis and AD pathology. Mn could also increase the aggregation of misfolded Aβ peptides in cholinergic neurons via the dysregulation of proteasome 20S and heat shock proteins [179]. These findings indicate that Mn may contribute to AD pathogenesis via the Mn-induced dysregulation of Aβ production.…”

Section: Aβ Aggregationmentioning

confidence: 86%

Manganese Accumulation in the Brain via Various Transporters and Its Neurotoxicity Mechanisms

et al. 2020

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Manganese (Mn) is an essential trace element, serving as a cofactor for several key enzymes, such as glutamine synthetase, arginase, pyruvate decarboxylase, and mitochondrial superoxide dismutase. However, its chronic overexposure can result in a neurological disorder referred to as manganism, presenting symptoms similar to those inherent to Parkinson’s disease. The pathological symptoms of Mn-induced toxicity are well-known, but the underlying mechanisms of Mn transport to the brain and cellular toxicity leading to Mn’s neurotoxicity are not completely understood. Mn’s levels in the brain are regulated by multiple transporters responsible for its uptake and efflux, and thus, dysregulation of these transporters may result in Mn accumulation in the brain, causing neurotoxicity. Its distribution and subcellular localization in the brain and associated subcellular toxicity mechanisms have also been extensively studied. This review highlights the presently known Mn transporters and their roles in Mn-induced neurotoxicity, as well as subsequent molecular and cellular dysregulation upon its intracellular uptakes, such as oxidative stress, neuroinflammation, disruption of neurotransmission, α-synuclein aggregation, and amyloidogenesis.

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“… 3 , 4 Heat shock proteins (HSPs) were reported to protect against ROS, toxic misfolded or aberrant proteins, and cell death. 5 HSP overexpression was associated with the induction of cell proliferation, migration, and invasion in different cancer types, like breast cancer. 6 , 7 HSP90 and HSP70 overexpression was reported to induce cell proliferation in human breast cancer tissues 8 , 9 and in MCF-7 and MDA-MB-231 cells.…”

mentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Produces Heat Shock Protein 90 and 70 Overexpression, Prostaglandin E2/Wnt/β-Catenin Signaling Disruption, and Cell Proliferation in MCF-7 and MDA-MB-231 Cells after 24 h and 14 Days of Chlorpyrifos Treatment

García

Moyano

Pelayo

et al. 2021

Chem. Res. Toxicol.

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The biocide chlorpyrifos (CPF) was described to increase breast cancer risk in humans, to produce breast cancer in animals, and to induce cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment. The entire mechanisms related to these CPF actions remain unknown. CPF induced cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment by AhR activation through the PGE2/Wnt/β-catenin pathway and HSP90 and HSP70 overexpression. Our results reveal new information on CPF toxic mechanisms induced in human breast cancer cell lines, which could assist in elucidating its involvement in breast cancer.

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Manganese increases Aβ and Tau protein levels through proteasome 20S and heat shock proteins 90 and 70 alteration, leading to SN56 cholinergic cell death following single and repeated treatment

Cited by 17 publications

References 106 publications

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Manganese Accumulation in the Brain via Various Transporters and Its Neurotoxicity Mechanisms

Aryl Hydrocarbon Receptor Activation Produces Heat Shock Protein 90 and 70 Overexpression, Prostaglandin E2/Wnt/β-Catenin Signaling Disruption, and Cell Proliferation in MCF-7 and MDA-MB-231 Cells after 24 h and 14 Days of Chlorpyrifos Treatment

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