The protective role of sesame oil against Parkinson's-like disease induced by manganese in rats.

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25 mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8 ml/kg of SO for 5 weeks. Mn-induced motor dysfunction was indicated by significant decreases in the time taken by rats to fall during the rotarod test and in the number of movements observed during the open field test. Also, Mn resulted in neuronal degeneration as observed by histological staining. The striatal levels of lipid peroxides and reduced glutathione (oxidative stress markers), interleukin-6 and tumor necrosis factor-α (inflammatory markers) were significantly elevated. Mn significantly reduced the levels of dopamine and Bcl-2, while GABA, PERK, ATF-6, Bax, and caspase-3 were increased. Interestingly, all SO doses, especially at 8 ml/kg, significantly improved locomotor activity, biochemical deviations and reduced neuronal degeneration. In conclusion, SO may provide potential therapeutic benefits in enhancing motor performance and promoting neuronal survival in individuals highly exposed to Mn.

AAV-mediated hepatic expression of SLC30A10 and the Thr95Ile variant attenuates manganese excess and other phenotypes in Slc30a10-deficient mice.

The manganese (Mn) export protein SLC30A10 is essential for Mn excretion via the liver and intestines. Patients with SLC30A10 deficiency develop Mn excess, dystonia, liver disease, and polycythemia. Recent genome-wide association studies revealed a link between the SLC30A10 variant T95I and markers of liver disease. The in vivo relevance of this variant has yet to be investigated. Using in vitro and in vivo models, we explore the impact of the T95I variant on SLC30A10 function. While SLC30A10 I95 expressed at lower levels than T95 in transfected cell lines, both T95 and I95 variants protected cells similarly from Mn-induced toxicity. Adeno-associated virus 8-mediated expression of T95 or I95 SLC30A10 using the liver-specific thyroxine binding globulin promoter normalized liver Mn levels in mice with hepatocyte Slc30a10 deficiency. Furthermore, Adeno-associated virus-mediated expression of T95 or I95 SLC30A10 normalized red blood cell parameters and body weights and attenuated Mn levels and differential gene expression in livers and brains of mice with whole body Slc30a10 deficiency. While our in vivo data do not indicate that the T95I variant significantly compromises SLC30A10 function, it does reinforce the notion that the liver is a key site of SLC30A10 function. It also supports the idea that restoration of hepatic SLC30A10 expression is sufficient to attenuate phenotypes in SLC30A10 deficiency.

NTRK1-mediated protection against manganese-induced neurotoxicity and cell apoptosis via IGF2 in SH-SY5Y cells.

BACKGROUND: Excessive manganese (Mn) exposure has been linked to neurotoxicity, cognitive impairments. Neurotrophic Receptor Kinase 1 (NTRK1) encodes Tropomyosin kinase A (TrkA), a neurotrophic receptor, as a mediator of neuron differentiation and survival. Insulin-like growth factor 2 (IGF2), a pivotal member of the insulin gene family, plays a crucial role in brain development and neuroprotection. Despite this knowledge, the precise mechanisms through which NTRK1 and IGF2 influence cell responses to Mn-induced neuronal damage remain elusive. METHODS: Cell apoptosis was assessed using CCK8, TUNEL staining, and Western blot analysis of cleaved Caspase-3. Lentiviral vectors facilitated NTRK1 overexpression, while small interfering RNAs (siRNAs) facilitated IGF2 knockdown. Real-time Quantitative PCR (qPCR) determined gene expression levels, while Western blotting measured protein expression. RESULTS: The study reveals that NTRK1 inhibits MnCl2-induced apoptosis in SH-SY5Y cells. NTRK1 overexpression significantly upregulated IGF2 expression, and subsequent siRNA-IGF2 experiments confirmed IGF2's pivotal role in NTRK1-mediated neuroprotection. Notably, the study identifies that NTRK1 regulates the expression of IGF2 in the neuroprotective mechanism with the involvement of ER stress pathways. DISCUSSION: The study reveals NTRK1's neuroprotective role via IGF2 against Mn-induced neurotoxicity and ER stress modulation in SH-SY5Y cells. These findings offer insights into potential therapies for neurodegenerative disorders related to Mn exposure and NTRK1 dysfunction, driving future research in this domain.

Impact of manganese accumulation on Na,K-ATPase expression and function in the cerebellum and striatum of C57Bl/6 mice.

Overexposure to Mn causes a neurological disorder-manganism-with motor symptoms that overlap closely with disorders associated with haploinsufficiency in the gene encoding for α3 isoform of Na+,K+-ATPase (NKA). The present study was designed to test the hypothesis that behavioral changes in the mouse model of manganism may be associated with changes in the expression and activity of α3 NKA in the cerebellum (CB) and striatum (STR)-the key brain structures responsible for motor control in adult mice. C57Bl/6 mice were exposed to MnCl2 at 0.5 g/L (in drinking water) for up to eight weeks. After four weeks of Mn consumption, Mn levels were increased in the CB only. Behavioral tests demonstrated decreased performance of Mn-treated mice in the shuttle box test (third through sixth weeks), and the inclined grid walking test (first through sixth weeks), suggesting the development of learning impairment, decreased locomotion, and motor discoordination. The activity of NKA significantly decreased, and the expression of α1-α3 isoforms of NKA increased in the second week in the CB only. Thus, signs of learning and motor disturbances developing in this model of manganism are unlikely to be directly linked to disturbances in the expression or activity of NKA in the CB or STR. Whether these early changes may contribute to the pathogenesis of later behavioral deficits remains to be determined.

The role of microglial LRRK2 kinase in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction.

Chronic manganese (Mn) exposure can lead to manganism, a neurological disorder sharing common symptoms with Parkinson's disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1ß, and TNF-α in the striatum and midbrain of WT mice, and these effects were more pronounced in G2019S mice. BV2 microglia were transfected with human LRRK2 WT or G2019S, followed by Mn (250 µM) exposure to better characterize its mechanistic action. Mn increased TNF-α, IL-1ß, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was elevated further in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these effects in both genotypes. Moreover, the media from Mn-treated G2019S-expressing BV2 microglia caused greater toxicity to the cath.a-differentiated (CAD) neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10 which was exacerbated in G2019S. RAB10 played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway and NLRP3 inflammasome in microglia. Our novel findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation.

Preventive treatment with sodium para-aminosalicylic acid inhibits manganese-induced apoptosis and inflammation via the MAPK pathway in rat thalamus.

Excessive exposure to manganese (Mn) may lead to neurotoxicity, referred to as manganism. In several studies, sodium para-aminosalicylic acid (PAS-Na) has shown efficacy against Mn-induced neurodegeneration by attenuating the neuroinflammatory response. The present study investigated the effect of Mn on inflammation and apoptosis in the rat thalamus, as well as the underlying mechanism of the PAS-Na protective effect. The study consisted of sub-acute (Mn treatment for 4 weeks) and sub-chronic (Mn and PAS-Na treatment for 8 weeks) experiments. In the sub-chronic experiments, pro-inflammatory cytokines, namely tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and cyclooxygenase 2 (COX-2) were significantly increased in the Mn-exposed group compared to the control II. PAS-Na treatment led to a significant reduction in the Mn-induced neuroinflammation by inhibiting IL-1ß and COX-2 mRNA expression and reducing IL-1ß secretion and JNK/p38 MAPK pathway activity. Furthermore, immunohistochemical analysis showed that the expression of caspase-3 was significantly increased in both the sub-acute and sub-chronic experimental paradigms concomitant with a significant decrease in B-cell lymphoma 2 (Bcl-2) in the thalamus of Mn-treated rats. PAS-Na also decreased the expression levels of several apoptotic markers downstream of the MAPK pathway, including Bcl-2/Bax and caspase-3, while up-regulating anti-apoptotic Bcl-2 proteins. In conclusion, Mn exposure led to inflammation in the rat thalamus concomitant with apoptosis, which was mediated via the MAPK signaling pathway. PAS-Na treatment antagonized effectively Mn-induced neurotoxicity by inhibiting the MAPK activity in the same brain region.

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

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-1ß, 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.

D-Ribose-LCysteine attenuates manganese-induced cognitive and motor deficit, oxidative damage, and reactive microglia activation.

Due to overexposure, manganese (Mn) accumulation in the brain can trigger the inhibition of glutathione synthesis and lead to increased generation of reactive oxygen species (ROS) and oxidative stress. D-Ribose-L-Cysteine (RibCys) has been demonstrated to effectively support glutathione synthesis to scavenge ROS and protect cells from oxidative damage. In the present study, we examined the effects of RibCys on weight changes, cognitive and motor associated activities, oxidative stress markers, striatal and cortical histology, and microglia activation following Mn exposure. Rats were exposed to either saline, Mn or/and RibCys for two weeks. The Mn exposed rats received RibCys either as pre-, co-, or post-treatments. Mn caused a significant decrease in weight, memory and motor activities, increased lactate dehydrogenase level, overexpression of IBA1 reflecting microglia activation, and distortion of the neuronal cytoarchitecture of the striatum and motor cortex, respectively. Interventions with RibCys mitigated Mn-induced neurotoxic events. Our novel study demonstrates that RibCys effectively ameliorates the neurotoxicity following Mn treatment and maybe a therapeutic strategy against the neurological consequences of Mn overexposurec.

A Novel Selenium Polysaccharide Alleviates the Manganese (Mn)-Induced Toxicity in Hep G2 Cells and Caenorhabditis elegans.

Manganese (Mn) is now known to have a variety of toxicities, particularly when exposed to it in the workplace. However, there are still ineffective methods for reducing Mn's hazardous effects. In this study, a new selenium polysaccharide (Se-PCS) was developed from the shell of Camellia oleifera to reduce Mn toxicity in vitro and in vivo. The results revealed that Se-PCS may boost cell survival in Hep G2 cells exposed to Mn and activate antioxidant enzyme activity, lowering ROS and cell apoptosis. Furthermore, after being treated with Se-PCS, Caenorhabditis elegans survived longer under Mn stress. daf-16, a tolerant critical gene, was turned on. Moreover, the antioxidant system was enhanced as the increase in strong antioxidant enzyme activity and high expression of the sod-3, ctl-2, and gst-1 genes. A variety of mutations were also used to confirm that Se-PCS downregulated the insulin signaling pathway. These findings showed that Se-PCS protected Hep G2 cells and C. elegans via the insulin/IGF-1 signaling pathway and that it could be developed into a promising medication to treat Mn toxicity.

Curcumin protects against manganese-induced neurotoxicity in rat by regulating oxidative stress-related gene expression via H3K27 acetylation.

Long-term manganese exposure causes a neurodegenerative disorder referred to as manganese poisoning, but the mechanism remains unclear and no specific treatment is available. Oxidative stress is widely recognised as one of the main causes of manganese-induced neurotoxicity. In recent years, the role of histone acetylation in neurodegenerative diseases has been widely concerned. curcumin is a natural polyphenol compound extracted from the rhizome of turmeric and exhibits both antioxidant and neuroprotective properties. Therefore, we aimed to investigate whether and how curcumin protects against manganese-induced neurotoxicity from the perspective of histone acetylation, based on the reversibility of histone acetylation modification. In this study, rats were treated with or without curcumin and subjected to long-term manganese exposure. Results that treatment of manganese decreased the protein expression of H3K18 acetylation and H3K27 acetylation at the promoters of oxidative stress-related genes and inhibited the expression of these genes. Nevertheless, curcumin increased the H3K27 acetylation level at the manganese superoxide dismutase (SOD2) gene promoter and promoted the expression of SOD2 gene. Oxidative damage in the rat striatum as well as learning and memory dysfunction were ameliorated after curcumin treatment. Taken together, our results suggest that the regulation of oxidative stress by histone acetylation may be a key mechanism of manganese-induced neurotoxicity. In addition, curcumin ameliorates Mn-induced neurotoxicity may be due to alleviation of oxidative damage mediated by increased activation of H3K27 acetylation at the SOD2 gene promoter.

The Role of PTEN/PI3K/AKT Signaling Pathway in Apoptosis of Liver Cells in Cocks with Manganese Toxicity.

PTEN/PI3K/AKT signaling pathway is an important pathway for cell proliferation and apoptosis. Exposure to excess manganese (Mn) can cause damage in organisms. However, whether Mn toxicity can cause apoptosis is still not clear. In order to explore the mechanism of PTEN/PI3K/AKT signaling pathway responsible for Mn-induced apoptotic injury, 160 Hyline cocks were divided into four groups; there were the control group (Con group), the low-dose Mn group (L group), the medium-dose Mn group (M group), and the high-dose Mn group (H group). The cocks in Con group, L group, M group, and H group were fed with MnCl2 diet containing 100, 600, 900, and 1800 mg/kg, respectively. The growth status of cocks in each group was observed on days 30, 60, and 90. Thirty cocks were randomly selected from each group and sacrificed on day 90 for optical microscope observation and fluorescence microscopic observation, as well as for transcription-level expression of apoptosis-related genes and heat shock proteins (HSPs) in the liver. The results showed that the growth status of cocks was gradually depressed with the extension of feeding time and with the increase of Mn dose. On day 90, the results of optical microscope observation and fluorescence microscope observation showed that damage and apoptosis appeared in the cock liver cells under Mn exposure groups. The results of transcription-level detection of apoptosis-related genes and HSPs indicated that Mn exposure upregulated eleven pro-apoptotic genes (including RIP1, RIP3, MLKL, Bax, Caspase-3, FADD, Cyt-C, ERK, JNK, Caspase-8, and P38) and downregulated one anti-apoptotic gene Bcl-2, further meaning that exposure to Mn-induced apoptosis in cock liver cells and PTEN/PI3K/AKT signaling pathway took part in molecular mechanism of apoptosis caused by excess Mn. Moreover, in our experiment, the increase of four HSPs (including HSP27, HSP40, HSP60, and HSP70) was found after Mn treatment for 90 days, which indicated that Mn stress triggered HSPs and HSPs were involved in molecular mechanism of Mn poisoning in cock livers. In addition, we also found there was upregulated dose-dependent manner in fifteen detected genes and there was downregulated dose-dependent manner in Bcl-2, indicating that the apoptosis caused by Mn poisoning in cock liver cells was dose-dependent.

Manganese Encephalopathy Caused by Homemade Methcathinone (Ephedrone) Prevalence in Poland.

Manganese encephalopathy is a known disorder in occupational medicine. A serious phenomenon has been the emergence of manganese encephalopathy in intravenous users of homemade methcathinone (ephedrone). A short survey was developed for clinical environments dealing with people who use psychoactive substances. The data were obtained from 72 rehabilitation therapy centers. Surveys carried out in about a third of Polish centers dealing with providing medical assistance to people addicted to substances other than alcohol and tobacco have shown that over 4% of people treated there had symptoms of manganese encephalopathy, of which more than half are people in whom the probability of a clinical diagnosis of this disorder is significant. It has been shown that knowledge of manganese encephalopathy is none or minimal in more than 70% of the surveyed institutions. An urgent need for personnel training in this field was pointed out. Attention was paid to the importance of disseminating good review articles on new and dynamically developing problem phenomena.

Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.

N-Acetylcysteine Ameliorates Neurotoxic Effects of Manganese Intoxication in Rats: A Biochemical and Behavioral Study.

Clinical and experimental evidences reveal that excess exposure to manganese is neurotoxic and leads to cellular damage. However, the mechanism underlying manganese neurotoxicity remains poorly understood but oxidative stress has been implicated to be one of the key pathophysiological features related to it. The present study investigates the effects associated with manganese induced toxicity in rats and further to combat these alterations with a well-known antioxidant N-acetylcysteine which is being used in mitigating the damage by its radical scavenging activity. The study was designed to note the sequential changes along with the motor and memory dysfunction associated with biochemical and histo-pathological alterations following exposure and treatment for 2 weeks. The results so obtained showed decrease in the body weights, behavioral deficits with increased stress markers and also neuronal degeneration in histo-pathological examination after manganese intoxication in rats. To overcome the neurotoxic effects of manganese, N-acetylcysteine was used in the current study due to its pleiotropic potential in several pathological ailments. Taken together, N-acetylcysteine helped in ameliorating manganese induced neurotoxic effects by diminishing the behavioral deficits, normalizing acetylcholinesterase activity, and augmentation of redox status.

Neuroprotective effects of disubstituted dithiolethione ACDT against manganese-induced toxicity in SH-SY5Y cells.

Dithiolethiones are lipophilic, organosulfur compounds that activate the Nrf2 transcription factor causing an upregulation of various phase II antioxidant enzymes. A disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) retains the functional pharmacophore while also containing modifiable functional groups. Neuroprotection against autoimmune encephalomyelitis in vivo and 6-hydroxy dopamine (a model for Parkinson's disease) in vitro have been previously reported with ACDT. Manganese (Mn) is a metal essential for metabolic processes at low concentrations. Overexposure and accumulation of Mn leads to a neurological condition called manganism which shares pathophysiological sequelae with parkinsonism. Here we hypothesized ACDT to be protective against manganese-induced cytotoxicity. SH-SY5Y human neuroblastoma cells exposed to 300 µM MnCl2 displayed approximately 50% cell death, and a 24-h pretreatment with 75 µM ACDT significantly reversed this cytotoxicity. ACDT pretreatment was also found to increase total GSH levels (2.18-fold) and the protein levels of NADPH:quinone oxidoreductase-1 (NQO1) enzyme (6.33-fold), indicating an overall increase in the cells' antioxidant defense stores. A corresponding 2.32-fold reduction in the level of Mn-induced reactive oxygen species was also observed in cells pretreated with ACDT. While no changes were observed in the protein levels of apoptotic markers Bax and Bcl-2, pretreatment with 75 µM ACDT led to a 2.09-fold downregulation of ZIP14 import transporter, indicating a potential reduction in the cellular uptake of Mn as an additional neuroprotective mechanism. These effects did not extend to other transporters like the divalent metal transporter 1 (DMT1) or ferroportin. Collectively, ACDT showed substantial neuroprotection against Mn-induced cytotoxicity, opening a path for dithiolethiones as a potential novel therapeutic option against heavy metal neurotoxicity.

Hypermanganesemia Induced Chorea and Cognitive Decline in a Tea Seller.

Background: Manganese associated neurotoxicity and neurodegeneration is quite rare yet established neurological disorder. This neurotoxic element has predilection for depositing in basal ganglia structures, manifesting mainly as parkinsonian and dystonic movement disorders with behavioral abnormalities. Case report: We report a 40-year-old man who presented with a subacute onset bilateral, asymmetric hyperkinetic movement disorder (predominantly left sided chorea) with multi-domain cognitive impairment, dysarthria, and generalized rigidity. Clinical history and examination yielded multiple differential diagnoses including deposition and metabolic disorders, autoimmune and paraneoplastic encephalitis involving basal ganglia, and neurodegenerative disorders with chorea and cognitive impairment. However, magnetic resonance imaging was suggestive of paramagnetic substance deposition, which came out to be manganese after laboratory investigations. History, clinical examinations, and investigation results pointed towards a diagnosis of acquired hypermanganesemia due to over-ingestion of manganese containing substance (i.e., black tea). He was treated symptomatically and with chelation therapy (calcium disodium edetate). At the sixth month of follow-up, complete resolution of chorea, dysarthria and partial amelioration of rigidity were observed. His cognitive decline and behavioral abnormalities improved. Discussion: This is probably the first reported case of acquired hypermanganesemia that presented as a combination of asymmetric chorea and cognitive dysfunction with atypical imaging characteristics. The clinical picture mimicked that of Huntington's disease. We highlight the potential deleterious effects of an apparently "benign" non-alcoholic beverage (i.e., black tea) on cerebral metabolism.

Catecholamine oxidation-mediated transcriptional inhibition in Mn neurotoxicity.

Manganese (Mn) poisoning may result in a neurological disorder called manganism. Although the neurotoxic mechanism of Mn is unclear, oxidative stress may be involved based on the interactions between neurotransmitter catecholamines and metals such as iron. Here, we propose a novel mechanism in which Mn oxidizes catecholamines and inhibits cellular transcription. Mn accelerated the oxidation of adrenaline (Ad) and produced adrenochrome (AdC) more effectively than iron. Furthermore, the oxidation of DNA bases increased when Ad, Mn, and iron were present. However, despite the absence of iron, cell viability decreased in the presence of AdC or Ad with Mn, which suggests there is another mechanism independent of oxidative DNA damage. AdC or preincubated Ad with Mn reduced mRNA synthesis in T7 RNA polymerase-driven transcription. RNA synthesis decreased in AdC-treated cells dose-dependently. These results show that Mn disrupts neuronal function via catecholamine oxidation-mediated transcriptional inhibition.

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

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

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 YY1 flox/flox mice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. 3 weeks after adeno-associated viral (AAV) infusion, mice were exposed to 330 µg of 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 blotting, quantitative PCR, 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 impairment of motor functions, 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 histone deacetylases 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.