RARE DISEASE
Manganese poisoning
Manganese poisoning
Manganese poisoning
Synonyms: Manganese intoxication, Manganism
Synonyms: Manganese intoxication, Manganism
Synonyms: Manganese intoxication, Manganism
Drug discovery
1
drug
With orphan designation
Overview
Manganese poisoning (manganism) is a neurodegenerative disorder caused by excessive manganese exposure, typically through inhalation or ingestion. It manifests with Parkinsonian symptoms (bradykinesia, rigidity, gait disturbances) but differs by earlier psychiatric disturbances (psychosis, hallucinations), "cock-walk" gait, and poor response to dopaminergic therapy [1][2][6][20]. Chronic exposure damages the basal ganglia, leading to irreversible neurological deficits [9][16].
Burden
Neurological disability persists post-exposure, often requiring long-term care [1][16]
Environmental exposure linked to neurodevelopmental deficits in children (↓IQ, motor skills) and Parkinsonism-like morbidity in adults [6][9][12]
Occupational cases incur high healthcare costs and productivity loss, with ~2% of U.S. water systems exceeding safe Mn levels [6][9][14]
Categories: rare disorders due to toxic effects, rare neurological diseases
Research Papers
471 drug discovery papers about Manganese poisoning, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
471 drug discovery papers about Manganese poisoning, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Antioxidant and Anxiolytic Effects of Comenic Acid In Vivo and Cytoprotective Action In Vitro Against Manganese-Induced Neurotoxicity.
The study evaluated the effects of comenic acid (100 μM) on the intensity of oxidative processes in the midbrain, as well as on behavioral activity and learning in rats exposed to manganese chloride (MnCl2) at a dose corresponding to 100 mg Mn. Manganese intoxication over 42 days led to a significant increase in the level of chemiluminescence of midbrain tissue samples, along with decreased motor activity, increased anxiety, and impaired learning. Administration of comenic acid at a dose of 5 mg/kg starting from day 14 of intoxication largely prevented the induction of oxidative processes and maintained the behavioral and learning parameters at the control levels. It was also found that comenic acid (100 μM) prevented death of rat cerebellar neurons in vitro caused by 100 μM MnCl2.
2026-09-01 | Magnesium induces iron starvation and metabolic rewiring to support the viability of cell envelope mutants and antibiotic-stressed cells
ABSTRACT Magnesium supplementation permits deletion of otherwise essential genes involved in cell envelope biogenesis in the Gram-positive model bacterium Bacillus subtilis . Yet, the specific underlying mechanism has remained elusive. To address this key knowledge gap, we made use of a mutant lacking ezrA and gpsB . Deletion of both of these genes involved in cell wall synthesis leads to severe growth inhibition which is ameliorated by magnesium addition. Our results indicate that, in the absence of magnesium, this mutant contains elevated levels of labile iron, is impaired in activating the oxidative stress response, and displays extreme sensitivity to iron and manganese intoxication. Intriguingly, we find that an ezrA single deletion, but not gpsB , exhibits heightened susceptibility to excess iron and manganese. This observation allowed us to investigate the source of toxicity and how EzrA may support metal homeostasis. Our data suggests that the major contributor of ROS is the electron transport system involved in cellular respiration. Both genetic and chemical means to reprogram the cells in favor of fermentation alleviate the metal toxicity in cells lacking ezrA . Collectively, our data shows that magnesium limits iron availability and redirects metabolism towards pathways that are preferred during iron scarcity. Consequently, these mechanisms result in reduced ROS production and oxidative stress mitigation. This explains why magnesium supplementation may render essential genes dispensable. In support of this model, we find that addition of magnesium helps cells to circumvent lysis typically caused by the treatment of an antibiotic that disrupts cell wall synthesis. Taken together, our results suggest that unmitigated oxidative stress fueled by labile iron is likely responsible for the detrimental effects of specific gene disruptions and certain antibiotic treatments. By reducing the pool of free iron and reprogramming cellular metabolism, magnesium mitigates oxidative damage and protects cells from ROS-mediated death. IMPORTANCE Deletion of certain essential genes is possible in Bacillus subtilis in the presence of excess magnesium. However, the mechanism behind this is unknown. In this study, we found that cell wall synthesis mutants have increased free reactive iron and are ill-equipped to activate oxidative stress response pathways. Consequently, these mutants are highly susceptible to reactive oxygen species (ROS) specifically stemming from the electron transport system. Our results suggest that magnesium protects cell wall synthesis mutants by limiting free iron availability, activating mechanisms responsible for neutralizing oxidative stress, and redirecting metabolism toward pathways that limit ROS production. Together, these effects alleviate oxidative stress and explain how magnesium helps bypass the requirement of genes that are otherwise considered essential. Finally, our observation that magnesium negatively affects the efficacy of cell wall-targeting antibiotics supports the notion that free iron-dependent ROS serves as a major driver of cell death.
2026-05-12 | Docosahexaenoic acid attenuates anxiety-like behaviors and restores astrocytic function and serotonergic integrity following acute manganese exposure in mice.
Manganese (Mn) overexposure induces neurotoxicity characterized by motor and cognitive impairments, as well as anxiety-like behaviors. The current study aimed to investigate the neuroprotective effects of docosahexaenoic acid (DHA) against acute Mn-induced neurobehavioral and neuropathological alterations in adult Swiss mice. Animals were assigned to four groups: control, Mn-intoxicated, Mn + DHA-treated, and DHA-treated. Anxiety-like behaviors were assessed using the open field, elevated plus maze, and marble burying tests, alongside immunohistochemical analyses of astrocytes and serotonergic neurons. Mn-intoxicated mice exhibited heightened anxiety-like behaviors, reduced serotonergic neuronal labeling in the dorsal raphe nucleus (DRN), and increased astrocytic reactivity in the hippocampus, indicated by elevated glial fibrillary acidic protein (GFAP) immunoreactivity. DHA pretreatment significantly attenuated these behavioral deficits and neuropathological changes, suggesting protective effects against Mn-induced altered serotoninergic neurotransmission and astrocytic activation. Overall, acute Mn exposure was associated with anxiety-like behaviors, disrupted serotoninergic neurotransmission, and astrocytic morphological alterations, whereas DHA exerted robust neuroprotective effects. These findings highlight DHA as a potential therapeutic candidate for Mn-induced neurotoxicity.
2026-03-01 | MANGANISM ASSOCIATED WITH HEPATIC DYSFUNCTION IN A PATIENT WITH AIDS: CASE REPORT
Excess manganese in the human body – mainly from chronic or occupational exposure – is associated with numerous toxic effects, predominantly neurological, resembling Parkinson’s disease (rigidity, cognitive alterations, bradykinesia). Manganism results from manganese accumulation in the central nervous system, especially the basal ganglia, globus pallidus, subthalamic nucleus, and substantia nigra. M.C.M, female, 45 years old, diagnosed with AIDS in 2015 during neurotoxoplasmosis treatment. In 2021, met criteria for systemic lupus erythematosus and rheumatoid arthritis. On regular ART. In 2019, after methotrexate and azathioprine use for rheumatologic activity, she developed elevated transaminases without prior liver disease. In November 2024, after partial hepatic improvement, she developed confusion, vertigo, and tremor with bradykinesia, unresponsive to levodopa. Brain MRI showed bilateral T1 hyperintensity in the globus pallidus and hypointensity in supratentorial and capsular white matter, suggesting manganese deposition. CSF analysis was normal; serum manganese at the upper limit of normal, urinary within normal range. Liver biopsy showed drug-induced hepatitis. Four months later, she had a seizure followed by aspiration, requiring intubation, progressing to dialysis-dependent acute renal failure and death. Occupational exposure is the best-established risk factor for manganism; however, hepatic dysfunction also increases risk, regardless of metal overload. This report highlights the need to consider manganism in the differential diagnosis of neurological diseases in PLHIV with liver dysfunction.
2025-12-18 | Novel Insights Into Manganese Toxicity Mitigation: Biogenic Calcium Phosphate Nanoparticles Boost Antioxidant Defense and Gene Expression in Wheat.
Heavy metal contamination severely impacts global food safety because of its toxicity, bioaccumulation, and nonbiodegradability. Recently developed nanotechnology strategies, including the use of greenly synthesized nanoparticles, offer environmentally safe solutions. An experiment on wheat investigated how biogenic calcium phosphate nanoparticles (CaPNPs) can improve the cellular defense against manganese toxicity. Cultivated wheat plants were irrigated with 300 μM MnSO4 and treated with foliar spraying of biogenic CaPNPs, which were green synthesized using Jania rubens extract, at concentrations of 25, 75, and 150 mg L-1. The 21-day-old seedlings manifested manganese (Mn) poisoning, represented by a reduction in plant height as well as weight, photosynthetic pigments, and nonenzymatic antioxidants, in addition to an escalation in the oxidative stress indicators represented by reactive oxygen species (H2O2) and lipid peroxidation (LPO). Furthermore, an increase in the pool of antioxidant compounds as well as antioxidant enzymes, minerals, in addition to the total antioxidant capacity, was clearly promoted by CaPNP application, especially at 75 mg L-1, which was consistent with the control. Consequently, CaPNPs caused a significant reduction in Mn, H2O2, MDA, and their oxidative damage. Additionally, 75 mg L-1 CaPNPs stimulated the expression of anti-oxidative stress responsive genes, catalase (CAT) and superoxide dismutase (SOD), in addition to betaine aldehyde dehydrogenase (BADH) and mitogen-activated protein kinases (MAPKs). Therefore, the use of biogenic 75 mg L-1 CaPNPs as an eco-friendly nanofertilizer plays a crucial role in plants growing in Mn-contaminated soil by promoting their growth characteristics, counterbalancing oxidative damage, and provoking the activity of the antioxidant defense machinery.
gene therapies
2025-03-09 | Role of dopaminergic RE1-silencing transcription factor (REST) in manganese-induced behavioral deficits and dysregulating dopaminergic and serotonergic neurotransmission in mice.
Chronic exposure to elevated levels of manganese (Mn) induces manganism, a neurological disorder, exhibiting symptoms resembling Parkinson's disease (PD). Mn is well known to dysregulate dopaminergic (DAergic) function, while the repressor element-1 silencing transcription factor (REST) induces protection against Mn-induced toxicity and several neurodegenerative diseases, including PD and Alzheimer's disease. In the present study, we investigated if DAergic REST plays a role in Mn-induced neurotoxicity by assessing behavioral deficits and alteration of neurotransmitter levels using high-performance liquid chromatography with electrochemical detector (HPLC-ECD), and microdialysis between DAergic-specific REST-deleted (REST cKO) mice and REST loxP mice as wild-type (WT) controls. Mice were exposed to Mn (330 μg, daily intranasal instillation for 3 weeks), followed by assessment of locomotor activity and novel object recognition, and subsequent brain dissection. Neurotransmitters, including DA, serotonin (5-HT), norepinephrine (NE), and glutamate, were analyzed in different brain regions, such as the striatum, midbrain, cortex, hippocampus, and cerebellum. After Mn exposure, extracellular DA levels in the striatum were measured by HPLC-microdialysis. The results showed that DAergic REST deletion exacerbated Mn-induced behavioral deficits and decreased DA levels in the nigrostriatal regions of WT mice. REST cKO increased DA turnover rates (DOPAC/DA and HVA/DA) by 10-fold in the nigrostriatal regions, showing lesser effects in other brain regions. Mn decreased extracellular DA levels, as measured by microdialysis, in the striatum in both genotypes. Mn decreased cortical NE levels in both genotypes and further exacerbated in REST cKO, while Mn decreased nigrostriatal NE levels only in REST cKO mice. REST cKO reduced 5-HT levels in all brain regions tested compared to WT mice. Mn increased glutamate and GABA levels in the striatum and midbrain, while these Mn effects were not altered by REST cKO. Taken together, our findings demonstrate that DAergic REST deficiency exacerbates Mn-induced motor and cognitive deficits along with dysregulation of neurotransmitters, mainly DA, 5-HT, and NE, suggesting that DAergic REST is important in Mn-induced dysregulation of monoaminergic neurotransmission.
2024-08-24 | Dopaminergic REST/NRSF is protective against manganese-induced neurotoxicity in mice.
Chronic exposure to elevated levels of manganese (Mn) may cause a neurological disorder referred to as manganism. The transcription factor REST is dysregulated in several neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. REST upregulated tyrosine hydroxylase and induced protection against Mn toxicity in neuronal cultures. In the present study, we investigated if dopaminergic REST plays a critical role in protecting against Mn-induced toxicity in vivo using dopaminergic REST conditional knockout (REST-cKO) mice and REST loxP mice as wild-type (WT) controls. Restoration of REST in the substantia nigra (SN) with neuronal REST AAV vector infusion was performed to further support the role of REST in Mn toxicity. Mice were exposed to Mn (330 μg, intranasal, daily for 3 weeks), followed by behavioral tests and molecular biology experiments. Results showed that Mn decreased REST mRNA/protein levels in the SN-containing midbrain, as well as locomotor activity and motor coordination in WT mice, which were further decreased in REST-cKO mice. Mn-induced mitochondrial insults, such as impairment of fission/fusion and mitophagy, apoptosis, and oxidative stress, in the midbrain of WT mice were more pronounced in REST-cKO mice. However, REST restoration in the SN of REST-cKO mice attenuated Mn-induced neurotoxicity. REST's molecular target for its protection is unclear, but REST attenuated Mn-induced mitochondrial dysregulation, indicating that it is a primary intracellular target for both Mn and REST. These novel findings suggest that dopaminergic REST in the nigrostriatal pathway is critical in protecting against Mn toxicity, underscoring REST as a potential therapeutic target for treating manganism.
2024-04-03 | 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.
2021-03-09 | 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.
2012-05-15 | Altered manganese homeostasis: Implications for BLI-3-dependent dopaminergic neurodegeneration and SKN-1 protection in C. elegans
The role of environmental factors in the etiology of neurodegenerative disorders, such as in Parkinson's disease (PD), has become increasingly imperative for examination, as genetics can only partially account for most cases. The heavy metal manganese (Mn) falls into this category of environmental contributors, as it is both essential but also neurotoxic upon overexposure and produces Parkinsonian symptomatology. In order to understand its toxicity, this review focuses on the various aspects of improper Mn homeostasis and its consequences using the genetically amenable Caenorhabditis elegans model. Namely, the roles of Mn transporter homologs for the divalent metal transporter 1 (DMT1) will be discussed, as Mn homeostasis is initially governed by proper cellular transport. Mn dyshomeostasis can result in enhanced oxidative stress through synergistic actions of dopamine oxidation that is dependent on the C. elegans dual oxidase BLI-3. Finally, neuroprotection conferred by the antioxidant transcription factor Nrf2 (C. elegans SKN-1) may signify a potential therapeutic approach against Mn toxicity.
cell therapies
2026-03-31 | Choroid plexus modulates subventricular zone adult neurogenesis and olfaction through secretion of small extracellular vesicles
The choroid plexus (CP) in the brain ventricles secretes cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ). As the largest adult neurogenic region enriched with neural stem/progenitor cells (NSPCs), the SVZ supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. This report depicts the presence of a CP-SVZ regulatory (CSR) axis, in which the CP regulates SVZ adult neurogenesis and olfaction via secretion of small extracellular vesicles (sEVs). The proposed CSR axis was supported by the evidence of (1) a direct effect of CP epithelial cells on the SVZ by in vivo transplantation and in vitro CP-SVZ co-culture assays, (2) differential OB neurogenesis following intracerebroventricular (ICV) infusion of sEVs derived from the CP of control or manganese (Mn)-poisoned mice, (3) progressively diminished SVZ adult neurogenesis after CP-selective inhibition of sEV secretion via AAV5-mediated SMPD3 knockdown, and (4) compromised olfactory performance following CP-selective SMPD3-knockdown. Collectively, our findings demonstrate the physiological, toxicological, and behavioral importance of this sEV-dependent CSR axis in the adult brain.
2025-09-08 | An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.
Manganese (Mn) is an essential trace metal required for normal biological function, yet it also poses neurotoxic risks when dysregulated. Maintaining proper intracellular and extracellular Mn levels is critical, as Mn imbalance has been implicated in a spectrum of human diseases-including inherited Mn transport disorders, acquired manganism, and more prevalent neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Despite these associations, the cellular mechanisms driving Mn-induced neuropathology remain poorly understood. To investigate this, we developed an induced pluripotent stem cell (iPSC)-derived midbrain neuronal model using patient lines with mutations in SLC39A14, SLC39A8, and SLC30A10. Through integrated transcriptomic and functional analyses, we found that Mn dyshomeostasis disrupts essential neuronal pathways, including mitochondrial bioenergetics, calcium signaling, endocytosis, glycosylation, and stress responses-leading to early neurodegeneration. This humanized model advances our understanding of Mn's impact on neuronal health and disease and highlights potential molecular targets for future therapeutic interventions in Mn-related neurological disorders.
2025-06-01 | Bioremediation of Manganese by Thermophilic Bacterial Isolates of Tapt Kund, Soldhar, and Gauri Kund Hot Springs of Uttarakhand, India
Manganese (Mn) contamination in groundwater is a global concern due to its harmful effects. The high concentration of Mn2+ in humans creates memory issues, decreased fertility, appetite loss, sleeplessness, sperm abnormalities, and ‘Manganism’. In this study, the isolation of thermophiles was followed by their assessment for MIC (minimum inhibitory concentration) and Mn bioremediation. We have isolated a total of 11 Mn-resistant bacterial strains of thermophiles with the identification of their bioremediation potential from the Tapt Kund, Soldhar, and Gauri Kund hot springs of Uttarakhand, India. Out of 11 strains, three isolates (TA8, SA9, and GA7) were identified with the highest metal resistance properties for toxic Mn2+. The metal tolerance capabilities of the strains were evaluated through MIC and the metal biosorption rate was estimated by the live cells bioremediation through thermophilic bacteria. ICP-MS (inductively coupled plasma mass spectrometry) was used to assess the Mn2+ removal rate of bacterial bioremediation. It turned out that every strain exhibited promising bioremediation potential and proved Mn-resistant. The bacterial strain TA8 exhibits the highest MIC (600 µg.L-1.) with a bioremediation rate of 98.34% for Mn2+. The bacterial strain SA9 has a MIC value of 525 µg.L-1, with a biosorption rate of 77.74% for Mn2+. The bacterial strain GA7 has a MIC of 475 µg.L-1, with an efficiency rate of 61.17% for Mn2+ removal. The most promising strain of thermophilic bacteria for Mn2+ bioremediation is the TA8, which has demonstrated the highest potential (98.34%) out of all the tested strains. The findings may have public health implications, as reducing manganese levels in groundwater can help mitigate health risks associated with Mn exposure. Also, this research enriches our knowledge of microbial bioremediation and its potential applications in environmental management. Ultimately, this research could offer a novel, economical, and environmentally beneficial approach to managing metal toxicity
2021-08-31 | Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity
Manganese (Mn) is an essential metal, which at high exposures causes neurotoxic effects and neurodegeneration. The neurotoxic effects of Mn are mediated by neuroinflammation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, and other mechanisms. Recent findings have demonstrated the potential impact of Mn overexposure on gut microbiota dysbiosis, which is known to contribute to neurodegeneration via secretion of neuroactive and proinflammatory metabolites. Therefore, in this review, we discuss the existing data on the impact of Mn exposure on gut microbiota biodiversity, bacterial metabolite production, and gut wall permeability regulating systemic levels. Recent data have demonstrated that Mn exposure may affect gut microbiota biodiversity by altering the abundance of Shiegella, Ruminococcus, Dorea, Fusicatenibacter, Roseburia, Parabacteroides, Bacteroidetes, Firmicutes, Ruminococcaceae, Streptococcaceae, and other bacterial phyla. A Mn-induced increase in Bacteroidetes abundance and a reduced Firmicutes/Bacteroidetes ratio may increase lipopolysaccharide levels. Moreover, in addition to increased systemic lipopolysaccharide (LPS) levels, Mn is capable of potentiating LPS neurotoxicity. Due to the high metabolic activity of intestinal microflora, Mn-induced perturbations in gut microbiota result in a significant alteration in the gut metabolome that has the potential to at least partially mediate the biological effects of Mn overexposure. At the same time, a recent study demonstrated that healthy microbiome transplantation alleviates Mn-induced neurotoxicity, which is indicative of the significant role of gut microflora in the cascade of Mn-mediated neurotoxicity. High doses of Mn may cause enterocyte toxicity and affect gut wall integrity through disruption of tight junctions. The resulting increase in gut wall permeability further promotes increased translocation of LPS and neuroactive bacterial metabolites to the systemic blood flow, ultimately gaining access to the brain and leading to neuroinflammation and neurotransmitter imbalance. Therefore, the existing data lead us to hypothesize that gut microbiota should be considered as a potential target of Mn toxicity, although more detailed studies are required to characterize the interplay between Mn exposure and the gut, as well as its role in the pathogenesis of neurodegeneration and other diseases.
2021-03-01 | The gut microbiota attenuate neuroinflammation in manganese exposure by inhibiting cerebral NLRP3 inflammasome.
Manganese (Mn) exposure has been reported to cause neurodegenerative disorders. β-Amyloid (Aβ) induced Tau pathology in an NLRP3-dependent manner is at the heart of Alzheimer's and Parkinson's diseases. The gut microbiota plays a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities. In this study, we found that Mn exposure increases Aβ1-40 and Tau production in brain, and causes hippocampal degeneration and necrosis. Meanwhile, Mn exposure can stimulate neurotoxicity by increasing inflammation either in peripheral blood and CNS. Importantly, we found that transplantation of gut microbiota from normal rats into Mn exposure rats reduced Aβ and Tau expression, and the cerebral expression of NLRP3 was downregulated, and the expression of neuroinflammatory factors was also downregulated. Therefore, improving the composition of gut microbiota in Mn exposure rats can attenuate neuroinflammation, which is considered as a novel therapeutic strategy for Mn exposure by remodelling the gut microbiota.
proteins
2025-01-23 | Manganese exposure induces parkinsonism-like symptoms by Serpina3n-TFEB-v/p-ATPase signaling mediated lysosomal dysfunction.
Manganese (Mn) is a neurotoxin that has been etiologically linked to the development of neurodegenerative diseases in the case of overexposure. It is widely accepted that overexposure to Mn leads to manganism, which has clinical symptoms similar to Parkinson's disease (PD), and is referred to as parkinsonism. Astrocytes have been reported to scavenge and degrade extracellular α-synuclein (α-Syn) in the brain. However, the mechanisms of Mn-induced neurotoxicity associated with PD remain unclear. Serpina3n is highly expressed in astrocytes and has been implicated in several neuropathologies. The role Serpina3n plays in Mn neurotoxicity and PD pathogenesis is still unknown. Here, we used wild-type and Serpina3n knockout (KO) C57BL/6 J mice with i.p. injection of 32.5 mg/kg MnCl2 once a day for 6 weeks to elucidate the role of Serpina3n in Mn-caused neurotoxicity regarding parkinsonism pathogenesis. We performed behavioral tests (open field, suspension and pole-climbing tests) to observe Mn-induced motor changes, immunohistochemistry to detect Mn-induced midbrain changes, and Western blot to detect Mn-induced changes of protein expression. It was found that Serpina3n KO markedly alleviated Mn neurotoxicity in mice by attenuating midbrain dopaminergic neuron damage and ameliorating motor deficits. Furthermore, using immunofluorescence colocalization analysis, Western blot and quantitative real-time PCR on Mn-treated C8-D1A cells, we found that Serpina3n KO significantly improved astrocytic α-Syn clearance by suppressing Mn-induced lysosomal dysfunction. Reduced transcription factor EB (TFEB)-v/p-ATPase signaling is responsible for the impairment of the lysosomal acidic environment. These novel findings highlight Serpina3n as a detrimental factor in Mn neurotoxicity associated with parkinsonism, capture the novel role of Serpina3n in regulating lysosomal function, and provide a potential target for antagonizing Mn neurotoxicity and curing parkinsonism in humans.
2024-02-26 | The Bacillus subtilis yqgC-sodA operon protects magnesium-dependent enzymes by supporting manganese efflux.
Microbes encounter a myriad of stresses during their life cycle. Dysregulation of metal ion homeostasis is increasingly recognized as a key factor in host-microbe interactions. Bacterial metal ion homeostasis is tightly regulated by dedicated metalloregulators that control uptake, sequestration, trafficking, and efflux. Here, we demonstrate that deletion of the Bacillus subtilis yqgC-sodA (YS) complex operon, but not deletion of the individual genes, causes hypersensitivity to manganese (Mn). YqgC is an integral membrane protein of unknown function and SodA is a Mn-dependent superoxide dismutase (MnSOD). The YS strain has reduced expression of two Mn efflux proteins, MneP and MneS, consistent with the observed Mn sensitivity. The YS strain accumulated high levels of Mn, had increased reactive radical species (RRS), and had broad metabolic alterations that can be partially explained by the inhibition of Mg-dependent enzymes. Although the YS operon deletion strain and an efflux-deficient mneP mneS double mutant both accumulate Mn and have similar metabolic perturbations they also display phenotypic differences. Several mutations that suppressed Mn intoxication of the mneP mneS efflux mutant did not benefit the YS mutant. Further, Mn intoxication in the YS mutant, but not the mneP mneS strain, was alleviated by expression of Mg-dependent, chorismate-utilizing enzymes of the menaquinone, siderophore, and tryptophan (MST) family. Therefore, despite their phenotypic similarities, the Mn sensitivity in the mneP mneS and the yqgC-sodA deletion mutants results from distinct enzymatic vulnerabilities.
2023-12-07 | NTRK1-mediated protection against manganese-induced neurotoxicity and cell apoptosis via IGF2 in SH-SY5Y cells.
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. 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. 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. 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.
2022-08-16 | 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-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.
2022-06-09 | Suppression of axonal attractant netrin-1 injured dopaminergic neuronal and motor function of mice during manganese overexposure.
Manganese (Mn) can accumulate in the striatum through the blood-brain barrier and cause neurotoxicity. It is mainly due to the decrease of dopamine (DA) levels in the striatum, which leads to extrapyramidal dysfunction. Netrin-1, as an axon guidance factor, can regulate the normal transmission of DA. However, few people have explored the role of netrin-1 in Mn-induced neurotoxicity. The purpose of the present study is to verify whether overexposure of Mn inhibits the axon attractant netrin-1, thereby damaging dopaminergic neuronal and motor function of mice. Here, we found that excessive Mn exposure reduces the expression of striatum netrin-1, tyrosine hydroxylase, DA receptor D3, and dopamine transporter 1, and the levels of serum netrin-1, and promotes dopaminergic neuronal and striatum injury, leading to DA transmission and motor dysfunction. Notably, recombinant mouse netrin-1 protein significantly antagonized Mn-induced neurotoxicity. These findings suggest that netrin-1 participates in Mn-induced motor dysfunction. Our findings may provide an experimental basis for fully elucidating the effects of Mn-induced neurotoxicity.
other
2024-05-17 | Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels.
Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.
2022-12-02 | Manganese-induced α-synuclein overexpression promotes the accumulation of dysfunctional synaptic vesicles and hippocampal synaptotoxicity by suppressing Rab26-dependent autophagy in presynaptic neurons.
Manganese (Mn) overexposure induces learning and memory impairments in mice by disrupting the functions of synapses and synaptic vesicles (SVs) in the hippocampus, which is associated with α-synuclein (α-Syn) overexpression. Rab26-dependent autophagy is a key signaling step required for impaired SV clearance; however, it is unclear whether Mn-induced α-Syn overexpression is linked to dysregulated Rab26-dependent autophagy in presynaptic neurons. In this study, we developed manganism models in male C57BL/6 mice and hippocampal primary neurons to observe the associations between Mn-induced α-Syn overexpression and impaired SV accumulation. The results of the in vivo experiments showed that 100 and 200 μmol/kg Mn exposure significantly impaired memory and synaptic plasticity in the mice, which was related to the accumulation of impaired SVs in the hippocampus. Consistent with the in vivo outcomes, the level of in vitro injured SVs in the 50 and 100 μmol/L Mn-exposed neuron group were higher than that in the control group. Moreover, 100 μmol/L Mn suppressed the initiation of Rab26-dependent autophagy at the synapse. Then, we transfected neurons with LV-α-Syn short hairpin RNA (shRNA) and exposed the neurons to Mn for an additional 24 h. Surprisingly, the area of colocalization between Rab26 and Atg16L1 and the expression level of LC3II-positive SVs were both higher in Mn-exposed LV-α-Syn shRNA-transfected neurons than those in Mn-treated normal or Mn-treated LV-scrambled shRNA-transfected neurons. Thus, Mn-induced α-Syn overexpression was responsible for the dysregulation of Rab26-dependent autophagy, thereby promoting the accumulation of injured SVs, and causing synaptotoxicity and cognitive and memory deficits in mice.
2019-01-23 | Overexpression of miR-138-5p suppresses MnCl2 -induced autophagy by targeting SIRT1 in SH-SY5Y cells.
The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1.
2017-03-13 | Comprehensive investigation of aberrant microRNAs expression in cells culture model of MnCl2-induced neurodegenerative disease
Manganese (Mn) is required in various human physiological processes. Excessive Mn exposure causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson's disease (IPD). However, the detailed mechanism of Mn-induced neurotoxicity is not yet fully understood. MicroRNAs (miRNAs) play important roles in gene expression regulation, and miRNA expression profile provides additional biological and prognostic information of diseases. In our study, RNA sequencing was performed to profile miRNAs in the SH-SY5Y cells following MnCl2 treatment. Expressions of 73 miRNAs were altered following excessive Mn treatment. Furthermore, has-miR-4306 was identified to target 3'UTR of ATP13A2 (PARK9) directly. Inhibition of has-miR-4306 efficiently restored Mn-induced cytotoxicity. Thus, for the first time, we revealed the miRNA effects of Mn ions to neuron cells, highlighted the involvement of miRNA regulation in neurodegeneration caused by Mn exposure, and provided a potential application of miRNAs in future therapeutic intervention.
2009-10-01 | The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease
Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn2+ homeostasis and has recently been implicated in Fe2+-mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn2+ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn2+ also amplifies the DA neurotoxicity of the PD-associated protein α-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn2+- and PD-associated DA neuron vulnerability. Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn2+ homeostasis and has recently been implicated in Fe2+-mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn2+ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn2+ also amplifies the DA neurotoxicity of the PD-associated protein α-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn2+- and PD-associated DA neuron vulnerability.
small molecules
2026-09-22 | Antioxidant and Anxiolytic Effects of Comenic Acid In Vivo and Cytoprotective Action In Vitro Against Manganese-Induced Neurotoxicity.
The study evaluated the effects of comenic acid (100 μM) on the intensity of oxidative processes in the midbrain, as well as on behavioral activity and learning in rats exposed to manganese chloride (MnCl2) at a dose corresponding to 100 mg Mn. Manganese intoxication over 42 days led to a significant increase in the level of chemiluminescence of midbrain tissue samples, along with decreased motor activity, increased anxiety, and impaired learning. Administration of comenic acid at a dose of 5 mg/kg starting from day 14 of intoxication largely prevented the induction of oxidative processes and maintained the behavioral and learning parameters at the control levels. It was also found that comenic acid (100 μM) prevented death of rat cerebellar neurons in vitro caused by 100 μM MnCl2.
2026-09-01 | Magnesium induces iron starvation and metabolic rewiring to support the viability of cell envelope mutants and antibiotic-stressed cells
ABSTRACT Magnesium supplementation permits deletion of otherwise essential genes involved in cell envelope biogenesis in the Gram-positive model bacterium Bacillus subtilis . Yet, the specific underlying mechanism has remained elusive. To address this key knowledge gap, we made use of a mutant lacking ezrA and gpsB . Deletion of both of these genes involved in cell wall synthesis leads to severe growth inhibition which is ameliorated by magnesium addition. Our results indicate that, in the absence of magnesium, this mutant contains elevated levels of labile iron, is impaired in activating the oxidative stress response, and displays extreme sensitivity to iron and manganese intoxication. Intriguingly, we find that an ezrA single deletion, but not gpsB , exhibits heightened susceptibility to excess iron and manganese. This observation allowed us to investigate the source of toxicity and how EzrA may support metal homeostasis. Our data suggests that the major contributor of ROS is the electron transport system involved in cellular respiration. Both genetic and chemical means to reprogram the cells in favor of fermentation alleviate the metal toxicity in cells lacking ezrA . Collectively, our data shows that magnesium limits iron availability and redirects metabolism towards pathways that are preferred during iron scarcity. Consequently, these mechanisms result in reduced ROS production and oxidative stress mitigation. This explains why magnesium supplementation may render essential genes dispensable. In support of this model, we find that addition of magnesium helps cells to circumvent lysis typically caused by the treatment of an antibiotic that disrupts cell wall synthesis. Taken together, our results suggest that unmitigated oxidative stress fueled by labile iron is likely responsible for the detrimental effects of specific gene disruptions and certain antibiotic treatments. By reducing the pool of free iron and reprogramming cellular metabolism, magnesium mitigates oxidative damage and protects cells from ROS-mediated death. IMPORTANCE Deletion of certain essential genes is possible in Bacillus subtilis in the presence of excess magnesium. However, the mechanism behind this is unknown. In this study, we found that cell wall synthesis mutants have increased free reactive iron and are ill-equipped to activate oxidative stress response pathways. Consequently, these mutants are highly susceptible to reactive oxygen species (ROS) specifically stemming from the electron transport system. Our results suggest that magnesium protects cell wall synthesis mutants by limiting free iron availability, activating mechanisms responsible for neutralizing oxidative stress, and redirecting metabolism toward pathways that limit ROS production. Together, these effects alleviate oxidative stress and explain how magnesium helps bypass the requirement of genes that are otherwise considered essential. Finally, our observation that magnesium negatively affects the efficacy of cell wall-targeting antibiotics supports the notion that free iron-dependent ROS serves as a major driver of cell death.
2026-05-12 | Docosahexaenoic acid attenuates anxiety-like behaviors and restores astrocytic function and serotonergic integrity following acute manganese exposure in mice.
Manganese (Mn) overexposure induces neurotoxicity characterized by motor and cognitive impairments, as well as anxiety-like behaviors. The current study aimed to investigate the neuroprotective effects of docosahexaenoic acid (DHA) against acute Mn-induced neurobehavioral and neuropathological alterations in adult Swiss mice. Animals were assigned to four groups: control, Mn-intoxicated, Mn + DHA-treated, and DHA-treated. Anxiety-like behaviors were assessed using the open field, elevated plus maze, and marble burying tests, alongside immunohistochemical analyses of astrocytes and serotonergic neurons. Mn-intoxicated mice exhibited heightened anxiety-like behaviors, reduced serotonergic neuronal labeling in the dorsal raphe nucleus (DRN), and increased astrocytic reactivity in the hippocampus, indicated by elevated glial fibrillary acidic protein (GFAP) immunoreactivity. DHA pretreatment significantly attenuated these behavioral deficits and neuropathological changes, suggesting protective effects against Mn-induced altered serotoninergic neurotransmission and astrocytic activation. Overall, acute Mn exposure was associated with anxiety-like behaviors, disrupted serotoninergic neurotransmission, and astrocytic morphological alterations, whereas DHA exerted robust neuroprotective effects. These findings highlight DHA as a potential therapeutic candidate for Mn-induced neurotoxicity.
2026-03-01 | MANGANISM ASSOCIATED WITH HEPATIC DYSFUNCTION IN A PATIENT WITH AIDS: CASE REPORT
Excess manganese in the human body – mainly from chronic or occupational exposure – is associated with numerous toxic effects, predominantly neurological, resembling Parkinson’s disease (rigidity, cognitive alterations, bradykinesia). Manganism results from manganese accumulation in the central nervous system, especially the basal ganglia, globus pallidus, subthalamic nucleus, and substantia nigra. M.C.M, female, 45 years old, diagnosed with AIDS in 2015 during neurotoxoplasmosis treatment. In 2021, met criteria for systemic lupus erythematosus and rheumatoid arthritis. On regular ART. In 2019, after methotrexate and azathioprine use for rheumatologic activity, she developed elevated transaminases without prior liver disease. In November 2024, after partial hepatic improvement, she developed confusion, vertigo, and tremor with bradykinesia, unresponsive to levodopa. Brain MRI showed bilateral T1 hyperintensity in the globus pallidus and hypointensity in supratentorial and capsular white matter, suggesting manganese deposition. CSF analysis was normal; serum manganese at the upper limit of normal, urinary within normal range. Liver biopsy showed drug-induced hepatitis. Four months later, she had a seizure followed by aspiration, requiring intubation, progressing to dialysis-dependent acute renal failure and death. Occupational exposure is the best-established risk factor for manganism; however, hepatic dysfunction also increases risk, regardless of metal overload. This report highlights the need to consider manganism in the differential diagnosis of neurological diseases in PLHIV with liver dysfunction.
2025-12-18 | Novel Insights Into Manganese Toxicity Mitigation: Biogenic Calcium Phosphate Nanoparticles Boost Antioxidant Defense and Gene Expression in Wheat.
Heavy metal contamination severely impacts global food safety because of its toxicity, bioaccumulation, and nonbiodegradability. Recently developed nanotechnology strategies, including the use of greenly synthesized nanoparticles, offer environmentally safe solutions. An experiment on wheat investigated how biogenic calcium phosphate nanoparticles (CaPNPs) can improve the cellular defense against manganese toxicity. Cultivated wheat plants were irrigated with 300 μM MnSO4 and treated with foliar spraying of biogenic CaPNPs, which were green synthesized using Jania rubens extract, at concentrations of 25, 75, and 150 mg L-1. The 21-day-old seedlings manifested manganese (Mn) poisoning, represented by a reduction in plant height as well as weight, photosynthetic pigments, and nonenzymatic antioxidants, in addition to an escalation in the oxidative stress indicators represented by reactive oxygen species (H2O2) and lipid peroxidation (LPO). Furthermore, an increase in the pool of antioxidant compounds as well as antioxidant enzymes, minerals, in addition to the total antioxidant capacity, was clearly promoted by CaPNP application, especially at 75 mg L-1, which was consistent with the control. Consequently, CaPNPs caused a significant reduction in Mn, H2O2, MDA, and their oxidative damage. Additionally, 75 mg L-1 CaPNPs stimulated the expression of anti-oxidative stress responsive genes, catalase (CAT) and superoxide dismutase (SOD), in addition to betaine aldehyde dehydrogenase (BADH) and mitogen-activated protein kinases (MAPKs). Therefore, the use of biogenic 75 mg L-1 CaPNPs as an eco-friendly nanofertilizer plays a crucial role in plants growing in Mn-contaminated soil by promoting their growth characteristics, counterbalancing oxidative damage, and provoking the activity of the antioxidant defense machinery.
gene therapies
2025-03-09 | Role of dopaminergic RE1-silencing transcription factor (REST) in manganese-induced behavioral deficits and dysregulating dopaminergic and serotonergic neurotransmission in mice.
Chronic exposure to elevated levels of manganese (Mn) induces manganism, a neurological disorder, exhibiting symptoms resembling Parkinson's disease (PD). Mn is well known to dysregulate dopaminergic (DAergic) function, while the repressor element-1 silencing transcription factor (REST) induces protection against Mn-induced toxicity and several neurodegenerative diseases, including PD and Alzheimer's disease. In the present study, we investigated if DAergic REST plays a role in Mn-induced neurotoxicity by assessing behavioral deficits and alteration of neurotransmitter levels using high-performance liquid chromatography with electrochemical detector (HPLC-ECD), and microdialysis between DAergic-specific REST-deleted (REST cKO) mice and REST loxP mice as wild-type (WT) controls. Mice were exposed to Mn (330 μg, daily intranasal instillation for 3 weeks), followed by assessment of locomotor activity and novel object recognition, and subsequent brain dissection. Neurotransmitters, including DA, serotonin (5-HT), norepinephrine (NE), and glutamate, were analyzed in different brain regions, such as the striatum, midbrain, cortex, hippocampus, and cerebellum. After Mn exposure, extracellular DA levels in the striatum were measured by HPLC-microdialysis. The results showed that DAergic REST deletion exacerbated Mn-induced behavioral deficits and decreased DA levels in the nigrostriatal regions of WT mice. REST cKO increased DA turnover rates (DOPAC/DA and HVA/DA) by 10-fold in the nigrostriatal regions, showing lesser effects in other brain regions. Mn decreased extracellular DA levels, as measured by microdialysis, in the striatum in both genotypes. Mn decreased cortical NE levels in both genotypes and further exacerbated in REST cKO, while Mn decreased nigrostriatal NE levels only in REST cKO mice. REST cKO reduced 5-HT levels in all brain regions tested compared to WT mice. Mn increased glutamate and GABA levels in the striatum and midbrain, while these Mn effects were not altered by REST cKO. Taken together, our findings demonstrate that DAergic REST deficiency exacerbates Mn-induced motor and cognitive deficits along with dysregulation of neurotransmitters, mainly DA, 5-HT, and NE, suggesting that DAergic REST is important in Mn-induced dysregulation of monoaminergic neurotransmission.
2024-08-24 | Dopaminergic REST/NRSF is protective against manganese-induced neurotoxicity in mice.
Chronic exposure to elevated levels of manganese (Mn) may cause a neurological disorder referred to as manganism. The transcription factor REST is dysregulated in several neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. REST upregulated tyrosine hydroxylase and induced protection against Mn toxicity in neuronal cultures. In the present study, we investigated if dopaminergic REST plays a critical role in protecting against Mn-induced toxicity in vivo using dopaminergic REST conditional knockout (REST-cKO) mice and REST loxP mice as wild-type (WT) controls. Restoration of REST in the substantia nigra (SN) with neuronal REST AAV vector infusion was performed to further support the role of REST in Mn toxicity. Mice were exposed to Mn (330 μg, intranasal, daily for 3 weeks), followed by behavioral tests and molecular biology experiments. Results showed that Mn decreased REST mRNA/protein levels in the SN-containing midbrain, as well as locomotor activity and motor coordination in WT mice, which were further decreased in REST-cKO mice. Mn-induced mitochondrial insults, such as impairment of fission/fusion and mitophagy, apoptosis, and oxidative stress, in the midbrain of WT mice were more pronounced in REST-cKO mice. However, REST restoration in the SN of REST-cKO mice attenuated Mn-induced neurotoxicity. REST's molecular target for its protection is unclear, but REST attenuated Mn-induced mitochondrial dysregulation, indicating that it is a primary intracellular target for both Mn and REST. These novel findings suggest that dopaminergic REST in the nigrostriatal pathway is critical in protecting against Mn toxicity, underscoring REST as a potential therapeutic target for treating manganism.
2024-04-03 | 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.
2021-03-09 | 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.
2012-05-15 | Altered manganese homeostasis: Implications for BLI-3-dependent dopaminergic neurodegeneration and SKN-1 protection in C. elegans
The role of environmental factors in the etiology of neurodegenerative disorders, such as in Parkinson's disease (PD), has become increasingly imperative for examination, as genetics can only partially account for most cases. The heavy metal manganese (Mn) falls into this category of environmental contributors, as it is both essential but also neurotoxic upon overexposure and produces Parkinsonian symptomatology. In order to understand its toxicity, this review focuses on the various aspects of improper Mn homeostasis and its consequences using the genetically amenable Caenorhabditis elegans model. Namely, the roles of Mn transporter homologs for the divalent metal transporter 1 (DMT1) will be discussed, as Mn homeostasis is initially governed by proper cellular transport. Mn dyshomeostasis can result in enhanced oxidative stress through synergistic actions of dopamine oxidation that is dependent on the C. elegans dual oxidase BLI-3. Finally, neuroprotection conferred by the antioxidant transcription factor Nrf2 (C. elegans SKN-1) may signify a potential therapeutic approach against Mn toxicity.
cell therapies
2026-03-31 | Choroid plexus modulates subventricular zone adult neurogenesis and olfaction through secretion of small extracellular vesicles
The choroid plexus (CP) in the brain ventricles secretes cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ). As the largest adult neurogenic region enriched with neural stem/progenitor cells (NSPCs), the SVZ supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. This report depicts the presence of a CP-SVZ regulatory (CSR) axis, in which the CP regulates SVZ adult neurogenesis and olfaction via secretion of small extracellular vesicles (sEVs). The proposed CSR axis was supported by the evidence of (1) a direct effect of CP epithelial cells on the SVZ by in vivo transplantation and in vitro CP-SVZ co-culture assays, (2) differential OB neurogenesis following intracerebroventricular (ICV) infusion of sEVs derived from the CP of control or manganese (Mn)-poisoned mice, (3) progressively diminished SVZ adult neurogenesis after CP-selective inhibition of sEV secretion via AAV5-mediated SMPD3 knockdown, and (4) compromised olfactory performance following CP-selective SMPD3-knockdown. Collectively, our findings demonstrate the physiological, toxicological, and behavioral importance of this sEV-dependent CSR axis in the adult brain.
2025-09-08 | An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.
Manganese (Mn) is an essential trace metal required for normal biological function, yet it also poses neurotoxic risks when dysregulated. Maintaining proper intracellular and extracellular Mn levels is critical, as Mn imbalance has been implicated in a spectrum of human diseases-including inherited Mn transport disorders, acquired manganism, and more prevalent neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Despite these associations, the cellular mechanisms driving Mn-induced neuropathology remain poorly understood. To investigate this, we developed an induced pluripotent stem cell (iPSC)-derived midbrain neuronal model using patient lines with mutations in SLC39A14, SLC39A8, and SLC30A10. Through integrated transcriptomic and functional analyses, we found that Mn dyshomeostasis disrupts essential neuronal pathways, including mitochondrial bioenergetics, calcium signaling, endocytosis, glycosylation, and stress responses-leading to early neurodegeneration. This humanized model advances our understanding of Mn's impact on neuronal health and disease and highlights potential molecular targets for future therapeutic interventions in Mn-related neurological disorders.
2025-06-01 | Bioremediation of Manganese by Thermophilic Bacterial Isolates of Tapt Kund, Soldhar, and Gauri Kund Hot Springs of Uttarakhand, India
Manganese (Mn) contamination in groundwater is a global concern due to its harmful effects. The high concentration of Mn2+ in humans creates memory issues, decreased fertility, appetite loss, sleeplessness, sperm abnormalities, and ‘Manganism’. In this study, the isolation of thermophiles was followed by their assessment for MIC (minimum inhibitory concentration) and Mn bioremediation. We have isolated a total of 11 Mn-resistant bacterial strains of thermophiles with the identification of their bioremediation potential from the Tapt Kund, Soldhar, and Gauri Kund hot springs of Uttarakhand, India. Out of 11 strains, three isolates (TA8, SA9, and GA7) were identified with the highest metal resistance properties for toxic Mn2+. The metal tolerance capabilities of the strains were evaluated through MIC and the metal biosorption rate was estimated by the live cells bioremediation through thermophilic bacteria. ICP-MS (inductively coupled plasma mass spectrometry) was used to assess the Mn2+ removal rate of bacterial bioremediation. It turned out that every strain exhibited promising bioremediation potential and proved Mn-resistant. The bacterial strain TA8 exhibits the highest MIC (600 µg.L-1.) with a bioremediation rate of 98.34% for Mn2+. The bacterial strain SA9 has a MIC value of 525 µg.L-1, with a biosorption rate of 77.74% for Mn2+. The bacterial strain GA7 has a MIC of 475 µg.L-1, with an efficiency rate of 61.17% for Mn2+ removal. The most promising strain of thermophilic bacteria for Mn2+ bioremediation is the TA8, which has demonstrated the highest potential (98.34%) out of all the tested strains. The findings may have public health implications, as reducing manganese levels in groundwater can help mitigate health risks associated with Mn exposure. Also, this research enriches our knowledge of microbial bioremediation and its potential applications in environmental management. Ultimately, this research could offer a novel, economical, and environmentally beneficial approach to managing metal toxicity
2021-08-31 | Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity
Manganese (Mn) is an essential metal, which at high exposures causes neurotoxic effects and neurodegeneration. The neurotoxic effects of Mn are mediated by neuroinflammation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, and other mechanisms. Recent findings have demonstrated the potential impact of Mn overexposure on gut microbiota dysbiosis, which is known to contribute to neurodegeneration via secretion of neuroactive and proinflammatory metabolites. Therefore, in this review, we discuss the existing data on the impact of Mn exposure on gut microbiota biodiversity, bacterial metabolite production, and gut wall permeability regulating systemic levels. Recent data have demonstrated that Mn exposure may affect gut microbiota biodiversity by altering the abundance of Shiegella, Ruminococcus, Dorea, Fusicatenibacter, Roseburia, Parabacteroides, Bacteroidetes, Firmicutes, Ruminococcaceae, Streptococcaceae, and other bacterial phyla. A Mn-induced increase in Bacteroidetes abundance and a reduced Firmicutes/Bacteroidetes ratio may increase lipopolysaccharide levels. Moreover, in addition to increased systemic lipopolysaccharide (LPS) levels, Mn is capable of potentiating LPS neurotoxicity. Due to the high metabolic activity of intestinal microflora, Mn-induced perturbations in gut microbiota result in a significant alteration in the gut metabolome that has the potential to at least partially mediate the biological effects of Mn overexposure. At the same time, a recent study demonstrated that healthy microbiome transplantation alleviates Mn-induced neurotoxicity, which is indicative of the significant role of gut microflora in the cascade of Mn-mediated neurotoxicity. High doses of Mn may cause enterocyte toxicity and affect gut wall integrity through disruption of tight junctions. The resulting increase in gut wall permeability further promotes increased translocation of LPS and neuroactive bacterial metabolites to the systemic blood flow, ultimately gaining access to the brain and leading to neuroinflammation and neurotransmitter imbalance. Therefore, the existing data lead us to hypothesize that gut microbiota should be considered as a potential target of Mn toxicity, although more detailed studies are required to characterize the interplay between Mn exposure and the gut, as well as its role in the pathogenesis of neurodegeneration and other diseases.
2021-03-01 | The gut microbiota attenuate neuroinflammation in manganese exposure by inhibiting cerebral NLRP3 inflammasome.
Manganese (Mn) exposure has been reported to cause neurodegenerative disorders. β-Amyloid (Aβ) induced Tau pathology in an NLRP3-dependent manner is at the heart of Alzheimer's and Parkinson's diseases. The gut microbiota plays a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities. In this study, we found that Mn exposure increases Aβ1-40 and Tau production in brain, and causes hippocampal degeneration and necrosis. Meanwhile, Mn exposure can stimulate neurotoxicity by increasing inflammation either in peripheral blood and CNS. Importantly, we found that transplantation of gut microbiota from normal rats into Mn exposure rats reduced Aβ and Tau expression, and the cerebral expression of NLRP3 was downregulated, and the expression of neuroinflammatory factors was also downregulated. Therefore, improving the composition of gut microbiota in Mn exposure rats can attenuate neuroinflammation, which is considered as a novel therapeutic strategy for Mn exposure by remodelling the gut microbiota.
proteins
2025-01-23 | Manganese exposure induces parkinsonism-like symptoms by Serpina3n-TFEB-v/p-ATPase signaling mediated lysosomal dysfunction.
Manganese (Mn) is a neurotoxin that has been etiologically linked to the development of neurodegenerative diseases in the case of overexposure. It is widely accepted that overexposure to Mn leads to manganism, which has clinical symptoms similar to Parkinson's disease (PD), and is referred to as parkinsonism. Astrocytes have been reported to scavenge and degrade extracellular α-synuclein (α-Syn) in the brain. However, the mechanisms of Mn-induced neurotoxicity associated with PD remain unclear. Serpina3n is highly expressed in astrocytes and has been implicated in several neuropathologies. The role Serpina3n plays in Mn neurotoxicity and PD pathogenesis is still unknown. Here, we used wild-type and Serpina3n knockout (KO) C57BL/6 J mice with i.p. injection of 32.5 mg/kg MnCl2 once a day for 6 weeks to elucidate the role of Serpina3n in Mn-caused neurotoxicity regarding parkinsonism pathogenesis. We performed behavioral tests (open field, suspension and pole-climbing tests) to observe Mn-induced motor changes, immunohistochemistry to detect Mn-induced midbrain changes, and Western blot to detect Mn-induced changes of protein expression. It was found that Serpina3n KO markedly alleviated Mn neurotoxicity in mice by attenuating midbrain dopaminergic neuron damage and ameliorating motor deficits. Furthermore, using immunofluorescence colocalization analysis, Western blot and quantitative real-time PCR on Mn-treated C8-D1A cells, we found that Serpina3n KO significantly improved astrocytic α-Syn clearance by suppressing Mn-induced lysosomal dysfunction. Reduced transcription factor EB (TFEB)-v/p-ATPase signaling is responsible for the impairment of the lysosomal acidic environment. These novel findings highlight Serpina3n as a detrimental factor in Mn neurotoxicity associated with parkinsonism, capture the novel role of Serpina3n in regulating lysosomal function, and provide a potential target for antagonizing Mn neurotoxicity and curing parkinsonism in humans.
2024-02-26 | The Bacillus subtilis yqgC-sodA operon protects magnesium-dependent enzymes by supporting manganese efflux.
Microbes encounter a myriad of stresses during their life cycle. Dysregulation of metal ion homeostasis is increasingly recognized as a key factor in host-microbe interactions. Bacterial metal ion homeostasis is tightly regulated by dedicated metalloregulators that control uptake, sequestration, trafficking, and efflux. Here, we demonstrate that deletion of the Bacillus subtilis yqgC-sodA (YS) complex operon, but not deletion of the individual genes, causes hypersensitivity to manganese (Mn). YqgC is an integral membrane protein of unknown function and SodA is a Mn-dependent superoxide dismutase (MnSOD). The YS strain has reduced expression of two Mn efflux proteins, MneP and MneS, consistent with the observed Mn sensitivity. The YS strain accumulated high levels of Mn, had increased reactive radical species (RRS), and had broad metabolic alterations that can be partially explained by the inhibition of Mg-dependent enzymes. Although the YS operon deletion strain and an efflux-deficient mneP mneS double mutant both accumulate Mn and have similar metabolic perturbations they also display phenotypic differences. Several mutations that suppressed Mn intoxication of the mneP mneS efflux mutant did not benefit the YS mutant. Further, Mn intoxication in the YS mutant, but not the mneP mneS strain, was alleviated by expression of Mg-dependent, chorismate-utilizing enzymes of the menaquinone, siderophore, and tryptophan (MST) family. Therefore, despite their phenotypic similarities, the Mn sensitivity in the mneP mneS and the yqgC-sodA deletion mutants results from distinct enzymatic vulnerabilities.
2023-12-07 | NTRK1-mediated protection against manganese-induced neurotoxicity and cell apoptosis via IGF2 in SH-SY5Y cells.
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. 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. 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. 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.
2022-08-16 | 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-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.
2022-06-09 | Suppression of axonal attractant netrin-1 injured dopaminergic neuronal and motor function of mice during manganese overexposure.
Manganese (Mn) can accumulate in the striatum through the blood-brain barrier and cause neurotoxicity. It is mainly due to the decrease of dopamine (DA) levels in the striatum, which leads to extrapyramidal dysfunction. Netrin-1, as an axon guidance factor, can regulate the normal transmission of DA. However, few people have explored the role of netrin-1 in Mn-induced neurotoxicity. The purpose of the present study is to verify whether overexposure of Mn inhibits the axon attractant netrin-1, thereby damaging dopaminergic neuronal and motor function of mice. Here, we found that excessive Mn exposure reduces the expression of striatum netrin-1, tyrosine hydroxylase, DA receptor D3, and dopamine transporter 1, and the levels of serum netrin-1, and promotes dopaminergic neuronal and striatum injury, leading to DA transmission and motor dysfunction. Notably, recombinant mouse netrin-1 protein significantly antagonized Mn-induced neurotoxicity. These findings suggest that netrin-1 participates in Mn-induced motor dysfunction. Our findings may provide an experimental basis for fully elucidating the effects of Mn-induced neurotoxicity.
other
2024-05-17 | Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels.
Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.
2022-12-02 | Manganese-induced α-synuclein overexpression promotes the accumulation of dysfunctional synaptic vesicles and hippocampal synaptotoxicity by suppressing Rab26-dependent autophagy in presynaptic neurons.
Manganese (Mn) overexposure induces learning and memory impairments in mice by disrupting the functions of synapses and synaptic vesicles (SVs) in the hippocampus, which is associated with α-synuclein (α-Syn) overexpression. Rab26-dependent autophagy is a key signaling step required for impaired SV clearance; however, it is unclear whether Mn-induced α-Syn overexpression is linked to dysregulated Rab26-dependent autophagy in presynaptic neurons. In this study, we developed manganism models in male C57BL/6 mice and hippocampal primary neurons to observe the associations between Mn-induced α-Syn overexpression and impaired SV accumulation. The results of the in vivo experiments showed that 100 and 200 μmol/kg Mn exposure significantly impaired memory and synaptic plasticity in the mice, which was related to the accumulation of impaired SVs in the hippocampus. Consistent with the in vivo outcomes, the level of in vitro injured SVs in the 50 and 100 μmol/L Mn-exposed neuron group were higher than that in the control group. Moreover, 100 μmol/L Mn suppressed the initiation of Rab26-dependent autophagy at the synapse. Then, we transfected neurons with LV-α-Syn short hairpin RNA (shRNA) and exposed the neurons to Mn for an additional 24 h. Surprisingly, the area of colocalization between Rab26 and Atg16L1 and the expression level of LC3II-positive SVs were both higher in Mn-exposed LV-α-Syn shRNA-transfected neurons than those in Mn-treated normal or Mn-treated LV-scrambled shRNA-transfected neurons. Thus, Mn-induced α-Syn overexpression was responsible for the dysregulation of Rab26-dependent autophagy, thereby promoting the accumulation of injured SVs, and causing synaptotoxicity and cognitive and memory deficits in mice.
2019-01-23 | Overexpression of miR-138-5p suppresses MnCl2 -induced autophagy by targeting SIRT1 in SH-SY5Y cells.
The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1.
2017-03-13 | Comprehensive investigation of aberrant microRNAs expression in cells culture model of MnCl2-induced neurodegenerative disease
Manganese (Mn) is required in various human physiological processes. Excessive Mn exposure causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson's disease (IPD). However, the detailed mechanism of Mn-induced neurotoxicity is not yet fully understood. MicroRNAs (miRNAs) play important roles in gene expression regulation, and miRNA expression profile provides additional biological and prognostic information of diseases. In our study, RNA sequencing was performed to profile miRNAs in the SH-SY5Y cells following MnCl2 treatment. Expressions of 73 miRNAs were altered following excessive Mn treatment. Furthermore, has-miR-4306 was identified to target 3'UTR of ATP13A2 (PARK9) directly. Inhibition of has-miR-4306 efficiently restored Mn-induced cytotoxicity. Thus, for the first time, we revealed the miRNA effects of Mn ions to neuron cells, highlighted the involvement of miRNA regulation in neurodegeneration caused by Mn exposure, and provided a potential application of miRNAs in future therapeutic intervention.
2009-10-01 | The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease
Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn2+ homeostasis and has recently been implicated in Fe2+-mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn2+ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn2+ also amplifies the DA neurotoxicity of the PD-associated protein α-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn2+- and PD-associated DA neuron vulnerability. Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn2+ homeostasis and has recently been implicated in Fe2+-mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn2+ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn2+ also amplifies the DA neurotoxicity of the PD-associated protein α-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn2+- and PD-associated DA neuron vulnerability.
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Drug Discovery Landscape
1 orphan drug designation for Manganese poisoning.
1 orphan drug designation for Manganese poisoning.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
trientine hydrochloride | small molecules | FDA | — | Cerberus Princeton, LLC |
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