Role of Astrocytes in Manganese Neurotoxicity Revisited

Ke, Tao; Sidoryk‐Węgrzynowicz, Marta; Pajarillo, Edward Alain B.; Rizor, Asha; Soares, Félix Alexandre Antunes; Lee, Eun-Sook; Aschner, Michael

doi:10.1007/s11064-019-02881-7

Cited by 26 publications

(13 citation statements)

References 114 publications

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“…Neuroinflammation is known to be one of the leading mechanisms of Mn-induced neurotoxicity [ 77 ] ( Figure 1 ). Astrocytes, and particularly astrocyte activation (astrogliosis), are considered as the mediator of neurotoxic and proinflammatory effect of manganese [ 78 ]. Particularly, in mixed glial cultures Mn-induced (0–100 μM Mn for 24 h) up-regulation of proinflammatory gene expression was shown to be associated with expression of astrocyte-specific genes and especially Ccl2, being indicative of the key role of astrocytes in Mn-induced neuroinflammation [ 79 ].…”

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

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%

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

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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“…Mn-induced excitotoxic neuronal injury may also be associated with astrocytic glutamate transporter impairment (15), but the mechanisms of Mn-induced dysregulation of glutamate neurotransmission has yet to be established. The glutamate aspartate transporter 1 (GLAST) and glutamate transporter 1 (GLT-1) are responsible for the majority of glutamate reuptake from the synaptic cleft, preventing the accumulation of excess glutamate (16)(17)(18)(19). GLAST and GLT-1 may be used interchangeably with their human homologs excitatory amino acid transporters 1 (EAAT1) and 2 (EAAT2), respectively.…”

mentioning

confidence: 99%

Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity

Pajarillo

Johnson

Rizor

et al. 2020

Journal of Biological Chemistry

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Manganese (Mn)-induced neurotoxicity resembles Parkinson’s disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week old YY1flox/floxmice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. Three weeks after AAV infusion, mice were exposed to 330 μg Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by western blot, qPCR and immunohistochemistry to assess YY1, TH, GLAST and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced (1) impairment of motor functions, (2) reduction of TH-expressing cells in SN and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with HDACs in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.

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“…The primers of 11 differentially expressed circRNAs that correlated with the occurrence of canine mammary tumour are listed in Table 1 . The relative expression of circRNAs was calculated to GPI [ 37 ]. Tissue from the tumour portion of the three samples was used as the experimental group, with adjacent normal tissue as the control.…”

Section: Methodsmentioning

confidence: 99%

CircRNA Expression Profiles in Canine Mammary Tumours

Zhu

et al. 2022

Veterinary Sciences

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Numerous studies have shown that the occurrence and development of tumours are associated with the expression of circular RNAs (circRNAs). However, the expression profile and clinical significance of circRNAs in canine mammary tumours remain unclear. In this paper, we collected tissue samples from three dogs with canine mammary tumours and analysed the expression profiles of circRNAs in these samples using high-throughput sequencing technology. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses revealed 14 biological processes associated with these genes, and 11 of these genes were selected for qRT-PCR to verify their authenticity. CircRNAs have sponge adsorption to miRNAs, so we constructed a circRNA-miRNA network map using Cytoscape software. As a result, we identified a total of 14,851 circRNAs in canine mammary tumours and its adjacent normal tissues. Of these, 106 were differentially expressed (fold change ≥ 2, p ≤ 0.05), and 64 were upregulated and 42 were downregulated. The GO analysis revealed that the biological processes involved were mainly in the regulation of the secretory pathway, the regulation of neurotransmitter secretion and the positive regulation of phagocytosis. Most of these biological pathways were associated with the cGMP-PKG (cyclic guanosine monophosphate) signalling pathway, the cAMP (cyclic adenosine monophosphate) signalling pathway and the oxytocin signalling pathway. After screening, source genes closely associated with canine mammary tumours were found to include RYR2, PDE4D, ROCK2, CREB3L2 and UBA3, and associated circRNAs included chr27:26618544-26687235-, chr26:8194880-8201833+ and chr17:7960861-7967766-. In conclusion, we reveals the expression profile of circRNAs in canine mammary tumours. In addition, some circRNAs might be used as potential biomarkers for molecular diagnosis.

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Role of Astrocytes in Manganese Neurotoxicity Revisited

Cited by 26 publications

References 114 publications

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

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

Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity

CircRNA Expression Profiles in Canine Mammary Tumours

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