scholarly journals Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks

Function ◽  
2021 ◽  
Vol 2 (2) ◽  
Author(s):  
Maosheng Xia ◽  
Shanshan Liang ◽  
Shuai Li ◽  
Ming Ji ◽  
Beina Chen ◽  
...  
Keyword(s):  
Risk Factor ◽  
Glial Cells ◽  
Neurological Diseases ◽  
Common Element ◽  
Neural Cells ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Excess Iron ◽  
Metal Implants

Abstract Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood–brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson’s disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.

scholarly journals Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

2020 ◽  
Author(s):  
Maosheng Xia ◽  
Shanshan Liang ◽  
Shuai Li ◽  
Zexiong Li ◽  
Manman Zhang ◽  
...  
Keyword(s):  
Glial Cells ◽  
Neurological Diseases ◽  
Common Element ◽  
Neural Cells ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Excess Iron ◽  
Metal Implants ◽  
Parkinson’S Diseases

ABSTRACTMetal implants are used worldwide, with millions of metal nails, plates and fixtures grafted during orthopaedic surgeries. Iron is the most common element of these metal implants. As time passes metal elements can be corroded and iron can be released from the implants in the form of ferric (Fe3+) or ferrous (Fe2+). These iron ions can permeate the surrounding tissues and enter circulation; importantly both Fe3+ and Fe2+ freely pass blood brain barrier (BBB). Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that the probability of metal implants delivered through orthopaedic surgeries was higher in patients of Parkinson’s diseases (PD) or ischemic stroke than in healthy subjects. This finding instigated subsequent study of iron effects on neuronal cells. In experiments in vivo, we found that iron selectively decreased presence of divalent metal transporter 1 (DMT1) in neurones through increasing the expression of Ndfip1, which degrades DMT1 and rarely exists in glial cells. At the same time iron accumulation increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microglial activation. Facing the attack of excess iron, glial cells act as neuroprotectors to uptake more extracellular iron by up-regulating DMT1, whereas neurones limit iron uptake through decreasing DMT1 operation. Cerebral accumulation of iron was associated with impaired cognition, locomotion and mood. Excess iron thus affects neural cells and could increase the risk of neurodegeneration.

scholarly journals Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

2019 ◽  
Vol 12 (603) ◽  
pp. eaay0300 ◽  
Author(s):  
Lucie I. Pisella ◽  
Jean-Luc Gaiarsa ◽  
Diabé Diabira ◽  
Jinwei Zhang ◽  
Ilgam Khalilov ◽  
...  
Keyword(s):  
Risk Factor ◽  
Social Behavior ◽  
Neurological Diseases ◽  
Ultrasonic Vocalizations ◽  
Network Activity ◽  
Gabaergic Inhibition ◽  
Developmental Sequence ◽  
Normal Cells ◽  
Neurological Pathology

KCC2 is a vital neuronal K+/Cl− cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007. We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.

DMT1-Mutant Erythrocytes Have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 957-957
Author(s):  
Zuzana Zidova ◽  
Pavla Pospisilova ◽  
Renata Mojzikova ◽  
Katarina Kapralova ◽  
Dalibor Dolezal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Life Span ◽  
Conflicts Of Interest ◽  
Transmembrane Protein ◽  
Erythroid Differentiation ◽  
Compound Heterozygous ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter

Abstract Divalent metal transporter 1 (DMT1, also known as NRAMP2 and SLC11A2) is a transmembrane protein important for intestinal iron (Fe2+) absorption and erythroid iron utilization. Homozygous or compound heterozygous mutations in DMT1 are associated with moderate to severe hypochromic microcytic anemia in human patients and a mouse model - mk/mk mice. We have previously reported that DMT1 deficiency leads to an impaired erythroid differentiation hallmarked by accumulation of immature forms of erythroblast which also showed increased rate of apoptosis. For human samples we observed suppression of colony-forming capacity of erythroid progenitors that can be corrected by the addition of iron saturated chelate Fe-SIH. Later we proved this result also for mk/mk progenitors and showed reduced number of mk/mk CFU-E (164±25 vs. 283±50) and BFU-E (9±4 vs. 22±5) colonies in comparison to the colonies of wild-type (wt) mice and improvement of the colony growth with Fe-SIH. In our following studies we focused on mature erythrocytes, the last stage of erythroid differentiation that has not been analyzed yet. We first determined the in vivo half-life of red blood cells (RBC). Isolated RBCs from mk/mk mice and wt controls were in vitro labeled with CFSE fluorescent dye and injected into the wt mice. The intensity of RBCs fluorescence was measured on the 1st, 7th, 10th, 14th, 19th, 26th and 30th day following the injection. We observed an accelerated clearance of CFSE-labeled mk/mk RBCs from circulating blood when compared to wt RBCs, which indicates increased destruction of DMT1-mutant erythrocytes in vivo. It is known, that mature RBCs retain the ability to undergo stress-induced death (eryptosis), characterized by their shrinkage, membrane blebbing and phosphatidylserine surface exposure. This process may be triggered by iron deficiency. To determine the involvement of eryptosis in mk/mk RBCs clearance, RBCs were exposed to different stress conditions in vitro. A significantly increased number of Annexin V-positive RBCs was detected for mk/mk RBCs when compared to wt RBCs after 5 and 7 hour exposure to hyperosmotic shock (400mM sucrose) and glucose depletion, respectively. These results indicate shortened life span of DMT1-mutant erythrocytes and their reduced ability to cope with stress. To unravel the possible underlying mechanisms we focus on two processes important for RBC survival; anti-oxidative defense and anaerobic glycolysis. We observed 1.5 to 2-fold higher activity of glutathione peroxidase, catalase and methemoglobin reductase and elevated levels of methemoglobin in mk/mk RBCs in comparison to wt RBCs, indicating increased oxidative stress in mk/mk RBCs. Increased activity of hexokinase (2.5 times) and pyruvatkinase (2.4 times) together with reduced ratio of ATP/ADP in mk/mk mice compared with wt mice (from 2.89±0.56 μmol/L to 1.71±0.49 μmol/L) shows enhanced demand for glycolytically derived ATP to maintain the stability of RBC membrane in mk/mk mice. Our analyzes suggest that DMT1 deficiency negatively affects metabolism and life span of mature erythrocytes; two other aspects of defective erythropoiesis contributing to the pathophysiology of the disease. Grant support Czech Grant Agency, grant No. P305/11/1745; Ministry of Health Czech Republic Grant No. NT11208 and Internal Grant of Palacky University Olomouc (LF_2013_010). Disclosures: No relevant conflicts of interest to declare.

Divalent metal transporter-1 decreases metal-related injury in the lung

2005 ◽  
Vol 289 (3) ◽  
pp. L460-L467 ◽  
Author(s):  
Andrew J. Ghio ◽  
Claude A. Piantadosi ◽  
Xinchao Wang ◽  
Lisa A. Dailey ◽  
Jacqueline D. Stonehuerner ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Metal Transport ◽  
Airway Epithelial Cells ◽  
Divalent Metal ◽  
Primary Role ◽  
Airway Epithelial ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Exposure to airborne particulates makes the detoxification of metals a continuous challenge for the lungs. Based on the fate of iron in airway epithelial cells, we postulated that divalent metal transporter-1 (DMT1) participates in detoxification of metal associated with air pollution particles. Homozygous Belgrade rats, which are functionally deficient in DMT1, exhibited diminished metal transport from the lower respiratory tract and greater lung injury than control littermates when exposed to oil fly ash. Preexposure of normal rats to iron in vivo increased expression of the isoform of DMT1 protein that lacked an iron-response element (−IRE), accelerated metal transport out of the lung, and decreased injury after particle exposure. In contrast, normal rats preexposed to vanadium showed less expression of the −IRE isoform of DMT1, decreased metal transport, and greater pulmonary injury after particle instillation. Respiratory epithelial cells in culture gave similar results. Also, DMT1 mRNA and protein expression for the −IRE isoform increased or decreased in these cells when exposed to iron or vanadium, respectively. These results thus demonstrate for the first time a primary role for DMT1 in lung metal transport and detoxification.

DMT1 Expression Is Regulated by DMT1 Associated Protein (DAP) in K562 Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2661-2661
Author(s):  
Yasumasa Okazaki ◽  
Hong Yin ◽  
Yuxiang Ma ◽  
Emiko Okazaki ◽  
Mary Yeh ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Protoporphyrin Ix ◽  
K562 Cells ◽  
Benzodiazepine Receptor ◽  
Mrna Levels ◽  
Intracellular Iron ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Excess Iron ◽  
C Terminus

Abstract While iron is essential for cell growth and survival excess iron through oxidative stress may produce hepatitic cirrhosis and hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy. Iron is absorbed across the duodenum with transport across the brush border mediated by DMT1 and across the basolateral surface by ferroportin with mechanisms that are inversely regulated by body iron concentrations. We have identified in rat intestine DAP, a novel protein that binds to the C-terminus of DMT1 (IRE) but not to the C-terminus of the non-IRE isoform (Blood, Nov 2004; 104: 53). DAP is a 526 amino acid protein that has been previously described as binding to the peripheral benzodiazepine receptor, an intrinsic mitochondrial protein involved in steriodogenesis and possibly in protoporphyrin IX transport into the mitochrondria. To investigate if DAP may have a role in regulation of intracellular iron transport DAP expression was down regulated using a vector containing a siRNA for DAP transfected into K562 cells by electroporation. Expression levels of DAP, transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1) and ferritin were examined by western blot and quantitative quantitivative PCR assays from days 1 to 6 after transfection. Following transfection with the DAP siRNA DAP mRNA levels were decreased 50% by day 1 with DAP protein levels decreasing by 50% at day 3. The DAP siRNA also decreased DMT1 protein expression by about 50% for the DMT1 (IRE) protein but had no effect on the protein derived from the non-IRE isoform. The leels of DMT1 mRNA were not affected by DAP siRNA. The decrease of DAP expression was not associated with any change in TfR1 or ferritin expression, suggesting that altered levels of DAP did not affect intracellular iron pools. Transfection with the DAP siRNA resulted also in more protean effects decreasing cell proliferation, the transition from S-phase to G2 in cell cycle, and protein synthesis. These data are consistent with DAP regulating DMT1 expression in K562 cells by modulating turnover of DMT1 (IRE) protein and also having more global effects on cellular metabolism.

Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4861-4864 ◽  
Author(s):  
Lydie Viatte ◽  
Jeanne-Claire Lesbordes-Brion ◽  
Dan-Qing Lou ◽  
Myriam Bennoun ◽  
Gaël Nicolas ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Genetic Disorder ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
The Common ◽  
Related Proteins ◽  
Deficient Mice

Abstract Evidence is accumulating that hepcidin, a liver regulatory peptide, could be the common pathogenetic denominator of all forms of iron overload syndromes including HFE-related hemochromatosis, the most prevalent genetic disorder characterized by inappropriate iron absorption. To understand the mechanisms whereby hepcidin controls iron homeostasis in vivo, we have analyzed the level of iron-related proteins by Western blot and immunohistochemistry in hepcidin-deficient mice, a mouse model of severe hemochromatosis. These mice showed important increased levels of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), and ferroportin compared with control mice. Interestingly, the level of ferroportin was coordinately up-regulated in the duodenum, the spleen, and the liver (predominantly in the Kupffer cells). Finally, we also evidenced a decrease of ceruloplasmin in the liver of hepcidin-deficient mice. We hypothesized that the deregulation of these proteins might be central in the pathogenesis of iron overload, providing key therapeutic targets for iron disorders. (Blood. 2005;105:4861-4864)

scholarly journals Gliogenic Potential of Single Pallial Radial Glial Cells in Lower Cortical Layers

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3237
Author(s):  
Ana Cristina Ojalvo-Sanz ◽  
Laura López-Mascaraque
Keyword(s):  
Glial Cell ◽  
Glial Cells ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Neural Cells ◽  
Cell Type ◽  
Cortical Layers ◽  
Radial Glial Cells ◽  
Radial Glial

During embryonic development, progenitor cells are progressively restricted in their potential to generate different neural cells. A specific progenitor cell type, the radial glial cells, divides symmetrically and then asymmetrically to produce neurons, astrocytes, oligodendrocytes, and NG2-glia in the cerebral cortex. However, the potential of individual progenitors to form glial lineages remains poorly understood. To further investigate the cell progeny of single pallial GFAP-expressing progenitors, we used the in vivo genetic lineage-tracing method, the UbC-(GFAP-PB)-StarTrack. After targeting those progenitors in embryonic mice brains, we tracked their adult glial progeny in lower cortical layers. Clonal analyses revealed the presence of clones containing sibling cells of either a glial cell type (uniform clones) or two different glial cell types (mixed clones). Further, the clonal size and rostro-caudal cell dispersion of sibling cells differed depending on the cell type. We concluded that pallial E14 neural progenitors are a heterogeneous cell population with respect to which glial cell type they produce, as well as the clonal size of their cell progeny.

scholarly journals Delivery Platforms for CRISPR/Cas9 Genome Editing of Glial Cells in the Central Nervous System

2021 ◽  
Vol 3 ◽  
Author(s):  
Vasco Meneghini ◽  
Marco Peviani ◽  
Marco Luciani ◽  
Giada Zambonini ◽  
Angela Gritti
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Gene Editing ◽  
Neuronal Damage ◽  
Neurological Diseases ◽  
Trophic Factors ◽  
Age Related ◽  
The Central Nervous System

Glial cells (astrocytes, oligodendrocytes, and microglia) are emerging as key players in several physiological and pathological processes of the central nervous system (CNS). Astrocytes and oligodendrocytes are not only supportive cells that release trophic factors or regulate energy metabolism, but they also actively modulate critical neuronal processes and functions in the tripartite synapse. Microglia are defined as CNS-resident cells that provide immune surveillance; however, they also actively contribute to shaping the neuronal microenvironment by scavenging cell debris or regulating synaptogenesis and pruning. Given the many interconnected processes coordinated by glial cells, it is not surprising that both acute and chronic CNS insults not only cause neuronal damage but also trigger complex multifaceted responses, including neuroinflammation, which can critically contribute to the disease progression and worsening of symptoms in several neurodegenerative diseases. Overall, this makes glial cells excellent candidates for targeted therapies to treat CNS disorders. In recent years, the application of gene editing technologies has redefined therapeutic strategies to treat genetic and age-related neurological diseases. In this review, we discuss the advantages and limitations of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based gene editing in the treatment of neurodegenerative disorders, focusing on the development of viral- and nanoparticle-based delivery methods for in vivo glial cell targeting.

TNF, IFN-γ, and endotoxin increase expression of DMT1 in bronchial epithelial cells

2005 ◽  
Vol 289 (1) ◽  
pp. L24-L33 ◽  
Author(s):  
Xinchao Wang ◽  
Michael D. Garrick ◽  
Funmei Yang ◽  
Lisa A. Dailey ◽  
Claude A. Piantadosi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Proinflammatory Cytokines ◽  
Airway Epithelial Cells ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Tnf Α ◽  
Ifn Γ

Regulation of the metal transport protein divalent metal transporter-1 (DMT1) may contribute to the uptake and detoxification of iron by cells resident in the respiratory tract. Inflammation has been associated with an increased availability of this metal resulting in an oxidative stress. Because proinflammatory cytokines and LPS have been demonstrated to affect an elevated expression of DMT1 in a macrophage cell line, we tested the hypothesis that tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and LPS increase DMT1 expression in airway epithelial cells. We used RT-PCR to detect mRNA for both −IRE DMT1 and +IRE DMT1 in BEAS-2B cells. Treatment with TNF-α, IFN-γ, or LPS increased both forms. Western blot analysis also demonstrated an increase in the expression of both isoforms of DMT1 after these treatments. Twenty-four hours after exposure of an animal model to TNF-α, IFN-γ, or LPS, a significant increase in pulmonary expression of −IRE DMT1 was seen by immunohistochemistry; the level of +IRE DMT1 was too low in the lung to be visualized using this methodology. Finally, iron transport into BEAS-2B cells was increased after inclusion of TNF-α, IFN-γ, or LPS in the media. We conclude that proinflammatory cytokines and LPS increase mRNA and protein expression of DMT1 in airway cells in vitro and in vivo. Furthermore, both −IRE and +IRE isoforms are elevated after exposures. Increased expression of this protein appears to be included in a coordinated response of the cell and tissue where the function might be to diminish availability of metal.

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