Brain manganese and the balance between essential roles and neurotoxicity

Balachandran, Rekha C.; Mukhopadhyay, Somshuvra; McBride, Danielle; Veevers, Jennifer; Harrison, Fiona E.; Aschner, Michael; Haynes, Erin N.; Bowman, Aaron B.

doi:10.1074/jbc.rev119.009453

Cited by 176 publications

(102 citation statements)

References 240 publications

(348 reference statements)

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“…It is a component of metalloenzymes such as superoxide dismutase, arginase and pyruvate carboxylase [ 24 ]. It is an essential micronutrient involved in the normal development of many organs including the brain [ 71 ]. A specific Mn deficiency syndrome has not been described in humans [ 24 ], although a recent study highlighted that Mn levels measured in hair were inversely correlated to the cognitive level in children of 2–4 years of age [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Fish-Based Baby Food Concern—From Species Authentication to Exposure Risk Assessment

et al. 2020

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In this work, two different but complementary approaches were used to evaluate the reliability of fish-based baby foods as a source of safe nourishment for babies. More specifically, barcoding analysis based on the Cytochrome Oxidase I sequences was used for fish species authentication and an analysis of metal/metalloid levels was performed to estimate the exposure risk assessment derived from consumption of selected fish-based baby food in infants and toddlers. COI DNA barcoding revealed that in three samples the species detected did not match the common name of the species shown on the label. In particular, G. chalcogrammus and M. australis were found in place of M. merluccius and O. mykiss was found in place of S. salar. The analysis of exposure risk assessment indicated a low risk for developing chronic systemic and carcinogenic effects in infants and toddler, under an exposure scenario based on daily consumption of a single box of fish-based baby food. However, it is important to highlight that in order to provide a comprehensive risk assessment it would be important to supplement the levels of exposure resulting from the total diet. Overall, our results suggest that more attention should be paid by authorities to ensure the safety of food for infants and toddlers.

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Section: Discussionmentioning

confidence: 99%

Fish-Based Baby Food Concern—From Species Authentication to Exposure Risk Assessment

et al. 2020

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“…SLC39A8 (aka ZIP8) is a transmembrane protein that cotransports divalent cations with bicarbonate; though it is capable of transporting Zn, Fe, Cu, Co, and Cd in cells, multiple studies suggest the primary physiologic role in humans is the transport of Mn 12 – 14 . Manganese is an essential trace element for human health and affects neuronal function and development of dopaminergic neurons, although excess Mn is associated with disease 15 – 18 . In the brain, Mn is at highest concentrations in the striatum, and Mn toxicity, also known as manganism , is characterized by a Parkinsonian phenotype resulting from dysfunction of the nigrostriatal pathway 16 .…”

Section: Introductionmentioning

confidence: 99%

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Mealer

Jenkins

Chen

et al. 2020

Sci Rep

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A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.

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“…The pathologies associated with dysregulation of Mn are interlinked with those of Fe due to their overlapping interactions in biological systems (72). Chronic overexposure to manganese is associated with broad neurological effects including impaired motor control and cognition (73). Fe accumulation in the brain is associated with Alzheimer's (AD) and Parkinson's (PD) diseases (74), and neurodegenerative effects are also linked to Mn accumulation, although direct links to AD and PD are less clear (73,75).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic overexposure to manganese is associated with broad neurological effects including impaired motor control and cognition (73). Fe accumulation in the brain is associated with Alzheimer's (AD) and Parkinson's (PD) diseases (74), and neurodegenerative effects are also linked to Mn accumulation, although direct links to AD and PD are less clear (73,75). Therefore interdependence between Fe and Mn (as well as other metals (75)) creates a delicate situation to navigate in the maintenance of homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Iron-mediated degradation of ribosomes under oxidative stress is attenuated by manganese

Smethurst

Kovalev

McKenzie

et al. 2020

Journal of Biological Chemistry

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Protein biosynthesis is fundamental to cellular life and requires the efficient functioning of the translational machinery. At the center of this machinery is the ribosome, a ribonucleoprotein complex that depends heavily on Mg2+ for structure. Recent work has indicated that other metal cations can substitute for Mg2+, raising questions about the role different metals may play in the maintenance of the ribosome under oxidative stress conditions. Here, we assess ribosomal integrity following oxidative stress both in vitro and in cells to elucidate details of the interactions between Fe2+ and the ribosome, and identify Mn2+ as a factor capable of attenuating oxidant-induced Fe2+-mediated degradation of rRNA. We report that Fe2+ promotes degradation of all rRNA species of the yeast ribosome and that it is bound directly to RNA molecules. Furthermore, we demonstrate that Mn2+ competes with Fe2+ for rRNA binding sites, and that protection of ribosomes from Fe2+-mediated rRNA hydrolysis correlates with the restoration of cell viability. Our data therefore suggest a relationship between these two transition metals in controlling ribosome stability under oxidative stress.

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Brain manganese and the balance between essential roles and neurotoxicity

Cited by 176 publications

References 240 publications

Fish-Based Baby Food Concern—From Species Authentication to Exposure Risk Assessment

Fish-Based Baby Food Concern—From Species Authentication to Exposure Risk Assessment

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Iron-mediated degradation of ribosomes under oxidative stress is attenuated by manganese

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