Manganese Neurotoxicity

Ávila, Daiana Silva; Puntel, Robson Luiz; Folmer, Vanderlei; Rocha, João Batista Teixeira da; Santos, A.P. Marreilha dos; Aschner, Michael

doi:10.1007/978-1-4614-5836-4_3

Cited by 8 publications

(7 citation statements)

References 126 publications

(136 reference statements)

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“…The actual causes of neurodegenerative diseases are unknown; however, it is believed that the major reason is genetic factors or age, and the second major reason for the disease is environmental factors such as neurotoxicant exposure. One of the best-known neurotoxicants is manganese; it is a kind of neurotoxicant whose exposure can produce a form of parkinsonism (also known as manganism) [ 5 ]. Manganese is an essential element for human metabolism [ 2 ].…”

Section: Resultsmentioning

confidence: 99%

“…Disease conditions related to intoxication with Mn are found to be harmful and could cause manganism [ 4 ]. Manganism is also called parkinsonism, because its symptoms are similar to those of Parkinson’s disease [ 5 ]. Manganese toxicity is thought to be mediated by oxidative stress, neuroinflammation, mitochondrial dysfunction, protein misfolding and apoptosis [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Manganism is also called parkinsonism, because its symptoms are similar to those of Parkinson’s disease [ 5 ]. Manganese toxicity is thought to be mediated by oxidative stress, neuroinflammation, mitochondrial dysfunction, protein misfolding and apoptosis [ 3 , 5 , 6 ]. Manganese can pass the blood–brain barrier in a DMT-1-mediated and/or transferrin-mediated pathway.…”

Section: Introductionmentioning

confidence: 99%

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Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

Singh

Shaikh

et al. 2022

IJMS

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Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1β) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl2-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

Singh

Shaikh

et al. 2022

IJMS

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“…Manganese and iron are also essential for mitochondrial respiration and cellular metabolism (Chen et al ; Levi & Rovida ; Mena et al ; Mühlenhoff et al ; Pierrel et al ). Together, these studies by others and us indicate that metal transporters play an important role in regulating diverse cognitive and metabolic functions in animals, and suggest that disruptions in the function of such transporters could lead to abnormal behavioral outcomes (Ávila et al ; Dusek et al ; Roels et al ; Søvik et al ; Su et al ). Consequently, here, we used the power of Drosophila genetics to investigate the cellular and molecular pathways that may explain the effects of Mvl on behavioral feeding decisions and organismal metabolic homeostasis.…”

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confidence: 82%

Drosophila divalent metal ion transporter Malvolio is required in dopaminergic neurons for feeding decisions

Søvik

LaMora

Seehra

et al. 2017

Genes Brain and Behavior

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Members of the Natural resistance-associated macrophage protein (NRAMP) family are evolutionarily-conserved metal ion transporters that play an essential role in regulating intracellular divalent cation homeostasis in both prokaryotes and eukaryotes. Malvolio (Mvl), the sole NRAMP family member in insects, plays a role in food choice behaviors in Drosophila and other species. However, the specific physiological and cellular processes that require the action of Mvl for appropriate feeding decisions remain elusive. Here we demonstrate that normal food choice requires Mvl function specifically in the dopaminergic system, and can be rescued by supplementing food with manganese. Collectively, our data indicate that the action of the Mvl transporter affects food choice behavior via the regulation of dopaminergic innervation of the mushroom bodies, a principle brain region associated with decision making in insects. Our studies suggest that the homeostatic regulation of the intra-neuronal levels of divalent cations plays an important role in the development and function of the dopaminergic system and associated behaviors.

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“…At the subcellular level, several studies have suggested that Mn could affect dopaminergic neurons by directly interacting with PD-related proteins such as α-Synuclein and PARK9 ( Gitler et al, 2009 ). Other studies in mammalian models suggested that Mn exposure leads to dopaminergic cell death via the upregulation of mitochondrial-derived oxidative stress ( Kitazawa et al, 2002 ; Erikson et al, 2004 ; Ávila et al, 2014 ). Recently, increased oxidative stress in response to Mn exposure has also been identified in the insect Drosophila melanogaster ( Mohandas et al, 2017 ).…”

Section: Cellular and Molecular Targets Of Manganese In The Insect Nementioning

confidence: 99%

The Impact of Environmental Mn Exposure on Insect Biology

Ben‐Shahar

2018

Front. Genet.

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Manganese (Mn) is an essential trace element that acts as a metal co-factor in diverse biochemical and cellular functions. However, chronic environmental exposure to high levels of Mn is a well-established risk factor for the etiology of severe, atypical parkinsonian syndrome (manganism) via its accumulation in the basal ganglia, pallidum, and striatum brain regions, which is often associated with abnormal dopamine, GABA, and glutamate neural signaling. Recent studies have indicated that chronic Mn exposure at levels that are below the risk for manganism can still cause behavioral, cognitive, and motor dysfunctions via poorly understood mechanisms at the molecular and cellular levels. Furthermore, in spite of significant advances in understanding Mn-induced behavioral and neuronal pathologies, available data are primarily for human and rodents. In contrast, the possible impact of environmental Mn exposure on brain functions and behavior of other animal species, especially insects and other invertebrates, remains mostly unknown both in the laboratory and natural habitats. Yet, the effects of environmental exposure to metals such as Mn on insect development, physiology, and behavior could also have major indirect impacts on human health via the long-term disruptions of food webs, as well as direct impact on the economy because of the important role insects play in crop pollination. Indeed, laboratory and field studies indicate that chronic exposures to metals such as Mn, even at levels that are below what is currently considered toxic, affect the dopaminergic signaling pathway in the insect brain, and have a major impact on the behavior of insects, including foraging activity of important pollinators such as the honey bee. Together, these studies highlight the need for a better understanding of the neuronal, molecular, and genetic processes that underlie the toxicity of Mn and other metal pollutants in diverse animal species, including insects.

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Manganese Neurotoxicity

Cited by 8 publications

References 126 publications

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

Drosophila divalent metal ion transporter Malvolio is required in dopaminergic neurons for feeding decisions

The Impact of Environmental Mn Exposure on Insect Biology

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