Neurotoxicity mechanisms of manganese in the central nervous system

Pajarillo, Edward Alain B.; Nyarko-Danquah, Ivan; Adinew, Getnet Mequanint; Rizor, Asha; Aschner, Michael; Lee, Eun-Sook

doi:10.1016/bs.ant.2020.11.003

Cited by 25 publications

(21 citation statements)

References 154 publications

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“…Mn is predominantly taken up by astrocytes among neural cell types in the brain (Aschner et al, 1999), implying that astrocytes may play a critical role in Mn‐induced neurotoxicity (Aschner et al, 1992). The molecular mechanisms of Mn‐induced toxicity in astrocytes have been reported, and they include mitochondrial dysfunction, oxidative stress, inflammation, and excitotoxicity (for review, see [Pajarillo, Nyarko‐Danquah, et al, 2021]), similar to human neurological disorders, including PD and AD (for review, see [Emerit et al, 2004]). Given these findings, it is vital to identify factors that play a critical role in the dysregulation of these molecular functions in multiple neurological disorders including Mn‐induced neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Deletion of RE1‐silencing transcription factor in striatal astrocytes exacerbates manganese‐induced neurotoxicity in mice

Pajarillo

Demayo

Digman

et al. 2022

Glia

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Chronic manganese (Mn) overexposure causes a neurological disorder, referred to as manganism, exhibiting symptoms similar to parkinsonism. Dysfunction of the repressor element‐1 silencing transcription factor (REST) is associated with various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Mn‐induced neurotoxicity, but its cellular and molecular mechanisms have yet to be fully characterized. Although neuronal REST is known to be neuroprotective, the role of astrocytic REST in neuroprotection remains to be established. We investigated if astrocytic REST in the striatal region of the mouse brain where Mn preferentially accumulates plays a role in Mn‐induced neurotoxicity. Striatal astrocytic REST was deleted by infusion of adeno‐associated viral vectors containing sequences of the glial fibrillary acidic protein promoter‐driven Cre recombinase into the striatum of RESTflox/flox mice for 3 weeks, followed by Mn exposure (30 mg/kg, daily, intranasally) for another 3 weeks. Striatal astrocytic REST deletion exacerbated Mn‐induced impairment of locomotor activity and cognitive function with further decrease in Mn‐reduced protein levels of tyrosine hydroxylase and glutamate transporter 1 (GLT‐1) in the striatum. Astrocytic REST deletion also exacerbated the Mn‐induced proinflammatory mediator COX‐2, as well as cytokines such as TNF‐α, IL‐1β, and IL‐6, in the striatum. Mn‐induced detrimental astrocytic products such as proinflammatory cytokines on neuronal toxicity were attenuated by astrocytic REST overexpression, but exacerbated by REST inhibition in an in vitro model using primary human astrocytes and Lund human mesencephalic (LUHMES) neuronal culture. These findings indicate that astrocytic REST plays a critical role against Mn‐induced neurotoxicity by modulating astrocytic proinflammatory factors and GLT‐1.

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Section: Introductionmentioning

confidence: 99%

Deletion of RE1‐silencing transcription factor in striatal astrocytes exacerbates manganese‐induced neurotoxicity in mice

Pajarillo

Demayo

Digman

et al. 2022

Glia

Self Cite

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“…Although there have been extensive studies to understand Mn-induced neurotoxicity, its molecular mechanisms involved are yet to be established. Mn is known to induce oxidative stress, mitochondrial impairment, inflammation, and autophagy dysfunction (for review, see (20)). In addition, growing evidence indicates that glutamate dysregulation and excitotoxicity play a critical role in Mn-induced neurotoxicity (13,21).…”

Section: Introductionmentioning

confidence: 99%

“…Mn is known to induce oxidative stress, mitochondrial impairment, inflammation, and autophagy dysfunction (for review, see Ref. ( 20 )). In addition, growing evidence indicates that glutamate dysregulation and excitotoxicity play a critical role in Mn-induced neurotoxicity ( 13 , 21 ).…”

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confidence: 99%

Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity

Pajarillo

Digman

Nyarko-Danquah

et al. 2021

Journal of Biological Chemistry

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Chronic exposure to high levels of manganese (Mn) leads to manganism, a neurological disorder with similar symptoms to those inherent to Parkinson's disease. However, the underlying mechanisms of this pathological condition have yet to be established. Since the human excitatory amino acid transporter 2 (EAAT2) (glutamate transporter 1 in rodents) is predominantly expressed in astrocytes and its dysregulation is involved in Mn-induced excitotoxic neuronal injury, characterization of the mechanisms that mediate the Mn-induced impairment in EAAT2 function is crucial for the development of novel therapeutics against Mn neurotoxicity. Repressor element 1-silencing transcription factor (REST) exerts protective effects in many neurodegenerative diseases. But the effects of REST on EAAT2 expression and ensuing neuroprotection are unknown. Given that the EAAT2 promoter contains REST binding sites, the present study investigated the role of REST in EAAT2 expression at the transcriptional level in astrocytes and Mn-induced neurotoxicity in an astrocyte–neuron coculture system. The results reveal that astrocytic REST positively regulates EAAT2 expression with the recruitment of an epigenetic modifier, cAMP response element-binding protein–binding protein/p300, to its consensus binding sites in the EAAT2 promoter. Moreover, astrocytic overexpression of REST attenuates Mn-induced reduction in EAAT2 expression, leading to attenuation of glutamate-induced neurotoxicity in the astrocyte–neuron coculture system. Our findings demonstrate that astrocytic REST plays a critical role in protection against Mn-induced neurotoxicity by attenuating Mn-induced EAAT2 repression and the ensuing excitotoxic dopaminergic neuronal injury. This indicates that astrocytic REST could be a potential molecular target for the treatment of Mn toxicity and other neurological disorders associated with EAAT2 dysregulation.

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“…This impairs the essential roles of neuron maintenance by disrupting glutamate/GABA-glutamine shuttling. The expression of EAAT1 and EAAT2 and the activity of glutamine synthetase can be downregulated by the excess of intra-astroglial heavy metals [ 334 , 335 , 336 , 337 ]. Thus, glutamine catabolism and elevated extracellular glutamate further induces excitotoxicity and neuronal damage, finally leading to neurodegeneration[ 334 , 338 , 339 ].…”

Section: Figurementioning

confidence: 99%

“…The expression of EAAT1 and EAAT2 and the activity of glutamine synthetase can be downregulated by the excess of intra-astroglial heavy metals [ 334 , 335 , 336 , 337 ]. Thus, glutamine catabolism and elevated extracellular glutamate further induces excitotoxicity and neuronal damage, finally leading to neurodegeneration[ 334 , 338 , 339 ]. Abbreviations: AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, DMT1: Divalent metal transporter 1, DAT: dopamine active transporter, EAAT: excitatory amino acid transporter, IL-1: Interleukin-1, IL-6: In-terleukin-6, IL-12: Interleukin-12, JAM: junctional adhesion molecule, LTP: Long term potentiation, MCU: mitochondrial calcium uniporter, MMP-9/-3: metalloproteinase-9/-3, MRP: Multidrug resistance-associated proteins, MTs: metallothioneins, NMDA: N-Methyl-D-Aspartic acid, NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase, NF-κB: nuclear factor kappa, PGE-2: Prostaglandin E2, PECAM: Platelet/endothelial cell adhesion mole-cule-1, ROS: Reactive oxygen species, TfR: Transferrin receptor, TNF: Tumor Necrosis Factor, VE-CADHERINE: vascular endothelial cadherin, ZIP: Zinc-imidazolate polymers, ZnT1: zinc transporter protein-1.…”

Section: Figurementioning

confidence: 99%

Parkinson’s Disease and the Metal–Microbiome–Gut–Brain Axis: A Systems Toxicology Approach

et al. 2021

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Parkinson’s Disease (PD) is a neurodegenerative disease, leading to motor and non-motor complications. Autonomic alterations, including gastrointestinal symptoms, precede motor defects and act as early warning signs. Chronic exposure to dietary, environmental heavy metals impacts the gastrointestinal system and host-associated microbiome, eventually affecting the central nervous system. The correlation between dysbiosis and PD suggests a functional and bidirectional communication between the gut and the brain. The bioaccumulation of metals promotes stress mechanisms by increasing reactive oxygen species, likely altering the bidirectional gut–brain link. To better understand the differing molecular mechanisms underlying PD, integrative modeling approaches are necessary to connect multifactorial perturbations in this heterogeneous disorder. By exploring the effects of gut microbiota modulation on dietary heavy metal exposure in relation to PD onset, the modification of the host-associated microbiome to mitigate neurological stress may be a future treatment option against neurodegeneration through bioremediation. The progressive movement towards a systems toxicology framework for precision medicine can uncover molecular mechanisms underlying PD onset such as metal regulation and microbial community interactions by developing predictive models to better understand PD etiology to identify options for novel treatments and beyond. Several methodologies recently addressed the complexity of this interaction from different perspectives; however, to date, a comprehensive review of these approaches is still lacking. Therefore, our main aim through this manuscript is to fill this gap in the scientific literature by reviewing recently published papers to address the surrounding questions regarding the underlying molecular mechanisms between metals, microbiota, and the gut–brain-axis, as well as the regulation of this system to prevent neurodegeneration.

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Neurotoxicity mechanisms of manganese in the central nervous system

Cited by 25 publications

References 154 publications

Deletion of RE1‐silencing transcription factor in striatal astrocytes exacerbates manganese‐induced neurotoxicity in mice

Deletion of RE1‐silencing transcription factor in striatal astrocytes exacerbates manganese‐induced neurotoxicity in mice

Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity

Parkinson’s Disease and the Metal–Microbiome–Gut–Brain Axis: A Systems Toxicology Approach

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