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Wang S, Li C, Fan W, Chen T, Xu W, Hu X, Wu Z, Xiao Z, Lin G, Ma B, Cheng L. Neurotrophin-3/chitosan inhibits cuproptosis-related genes to enable functional recovery after spinal cord injury. Int J Biol Macromol 2025; 310:143403. [PMID: 40268016 DOI: 10.1016/j.ijbiomac.2025.143403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 04/10/2025] [Accepted: 04/19/2025] [Indexed: 04/25/2025]
Abstract
OBJECTIVES This study investigated the regulatory mechanisms of cuproptosis-related genes (CRGs) in spinal cord injury (SCI) and explored the therapeutic potential of neurotrophin-3 (NT3)-loaded chitosan in promoting functional recovery. METHODS We conducted integrated bulk RNA-seq and single-cell RNA-seq (scRNA-seq) analyses of mouse spinal cord tissue at various time points after SCI. The key CRGs were identified using differential expression analysis, weighted gene co-expression network analysis, and machine learning. The therapeutic effects of NT3-loaded chitosan were evaluated using animal models and molecular docking analysis. RESULTS We identified four key CRGs (Atp7a, Cp, Loxl2, and Pde3b) and three key transcription factors (C/EBPα, Stat6, and Runx1) that were upregulated post-SCI, promoting cuproptosis and neuroinflammation. NT3-loaded chitosan treatment significantly inhibited CRG expression and enhanced functional recovery in the animal models. Molecular docking analysis demonstrated binding interactions between chitosan and key CRGs, suggesting a potential mechanism for their therapeutic effects. CONCLUSIONS Our findings highlight the critical role of CRGs in SCI progression and the potential of NT3-loaded chitosan as a therapeutic strategy for inhibiting cuproptosis and promoting functional recovery. Future studies should focus on validating these findings in larger cohorts and exploring the detailed mechanisms by which NT3-loaded chitosan modulates CRG expression.
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Affiliation(s)
- Siqiao Wang
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China
| | - Chen Li
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China
| | - Wenyong Fan
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China
| | - Tao Chen
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China
| | - Wei Xu
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China
| | - Xiao Hu
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China
| | - Zhourui Wu
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China
| | - Zhihui Xiao
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China
| | - Gufa Lin
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China.
| | - Bei Ma
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China.
| | - Liming Cheng
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China; Shanghai Research Center for Spine and Spinal Cord Diseases, Tongji University School of Medicine, Shanghai 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University School of Medicine, Shanghai 200065, China.
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Abstract
Iron accumulation in the CNS occurs in many neurological disorders. It can contribute to neuropathology as iron is a redox-active metal that can generate free radicals. The reasons for the iron buildup in these conditions are varied and depend on which aspects of iron influx, efflux, or sequestration that help maintain iron homeostasis are dysregulated. Iron was shown recently to induce cell death and damage via lipid peroxidation under conditions in which there is deficient glutathione-dependent antioxidant defense. This form of cell death is called ferroptosis. Iron chelation has had limited success in the treatment of neurological disease. There is therefore much interest in ferroptosis as it potentially offers new drugs that could be more effective in reducing iron-mediated lipid peroxidation within the lipid-rich environment of the CNS. In this review, we focus on the molecular mechanisms that induce ferroptosis. We also address how iron enters and leaves the CNS, as well as the evidence for ferroptosis in several neurological disorders. Finally, we highlight biomarkers of ferroptosis and potential therapeutic strategies.
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Affiliation(s)
- Samuel David
- Centre for Research in Neuroscience, and BRaIN Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Fari Ryan
- Centre for Research in Neuroscience, and BRaIN Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Priya Jhelum
- Centre for Research in Neuroscience, and BRaIN Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Antje Kroner
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA
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Yin Y, Peng J, Zhou J, Chen H, Peng D, Li D, Gan Y, Yin G, Tang Y. Tetrathiomolybdate Partially Alleviates Erectile Dysfunction of Type 1 Diabetic Rats Through Affecting Ceruloplasmin/eNOS and Inhibiting Corporal Fibrosis and Systemic Inflammation. Sex Med 2021; 10:100455. [PMID: 34818604 PMCID: PMC8847815 DOI: 10.1016/j.esxm.2021.100455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 11/28/2022] Open
Abstract
INTRODUCTION Patients with erectile dysfunction induced by diabetes mellitus (DMED) show a poor effect rate for oral phosphodiesterase type 5 inhibitors (PDE5is). Therefore, the new therapeutic strategy is necessary in patients with DMED. AIM To investigate whether Tetrathiomolybdate (TM) supplementation could ameliorate DMED by activation of eNOS. METHODS Twenty-four diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ) and the other 6 normal rats constituted the control group. Eight weeks later, the erectile function of rats was assessed with an apomorphine test. Only some rats with DMED were treated with TM orally every day for 4 weeks; the other rats remained in the same condition for 4 weeks. After 1 week washout, the erectile function of rats in each group was evaluated. Then, the serum concentration of IL-6 and histologic changes of corpus cavernosum were measured. MAIN OUTCOME MEASURE Erectile function was measured after DMED rats treated with TM. The cavernosum level of Ceruloplasmin (Cp), eNOS, endothelial cell content, corporal fibrosis, apoptosis rate and the serum level of IL-6 were also assayed. RESULTS Erectile function in the DMED group was significantly impaired compared with the control group and was partly, but significantly, improved in the DMED+TM group. The DMED group showed upregulation of Cp and inhibition of eNOS, but the inhibition was partly reversed in the DMED+TM group. The DMED group showed serious corporal fibrosis. However, TM supplementation partly increased the ratio of smooth muscle to collagen, decreased the ratio of apoptosis. What's more, gavage administration of TM profoundly decreased the serum level of IL-6 in DMED rats. CONCLUSION TM supplementation inhibits endothelial dysfunction, corporal fibrosis, and systemic inflammation, ultimately leading to partial improvement of DMED in rats. Yin Y, Peng J, Zhou J, et al., Tetrathiomolybdate Partially Alleviates Erectile Dysfunction of Type 1 Diabetic Rats Through Affecting Ceruloplasmin/eNOS and Inhibiting Corporal Fibrosis and Systemic Inflammation. Sex Med 2021;XX:XXXXXX.
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Affiliation(s)
- Yinghao Yin
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jingxuan Peng
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jun Zhou
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hanfei Chen
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dongyi Peng
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dongjie Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China; Xiangya International Medical Center, Department of Geriatric Urology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Yu Gan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Guangming Yin
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China.
| | - Yuxin Tang
- Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
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Looking for a partner: ceruloplasmin in protein-protein interactions. Biometals 2019; 32:195-210. [PMID: 30895493 DOI: 10.1007/s10534-019-00189-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 03/18/2019] [Indexed: 10/27/2022]
Abstract
Ceruloplasmin (CP) is a mammalian blood plasma ferroxidase. More than 95% of the copper found in plasma is carried by this protein, which is a member of the multicopper oxidase family. Proteins from this group are able to oxidize substrates through the transfer of four electrons to oxygen. The essential role of CP in iron metabolism in humans is particularly evident in the case of loss-of-function mutations in the CP gene resulting in a neurodegenerative syndrome known as aceruloplasminaemia. However, the functions of CP are not limited to the oxidation of ferrous iron to ferric iron, which allows loading of the ferric iron into transferrin and prevents the deleterious reactions of Fenton chemistry. In recent years, a number of novel CP functions have been reported, and many of these functions depend on the ability of CP to form stable complexes with a number of proteins.
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Zanardi A, Conti A, Cremonesi M, D'Adamo P, Gilberti E, Apostoli P, Cannistraci CV, Piperno A, David S, Alessio M. Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO Mol Med 2019; 10:91-106. [PMID: 29183916 PMCID: PMC5760856 DOI: 10.15252/emmm.201708361] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.
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Affiliation(s)
- Alan Zanardi
- Proteome Biochemistry, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Conti
- Proteome Biochemistry, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Marco Cremonesi
- Proteome Biochemistry, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Patrizia D'Adamo
- Molecular Genetics of Intellectual Disabilities, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Enrica Gilberti
- Unit of Occupational Health and Industrial Hygiene, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Pietro Apostoli
- Unit of Occupational Health and Industrial Hygiene, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Carlo Vittorio Cannistraci
- Biomedical Cybernetics Group, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Department of Physics, Technische Universität Dresden, Dresden, Germany.,Brain Bio-Inspired Computation (BBC) Lab, IRCCS Centro Neurolesi "Bonino Pulejo", Messina, Italy
| | - Alberto Piperno
- School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.,Centre for Diagnosis and Treatment of Hemochromatosis, ASST-S.Gerardo Hospital, Monza, Italy
| | - Samuel David
- Center for Research in Neuroscience, The Research Institute of The McGill University Health Center, Montreal, QC, Canada
| | - Massimo Alessio
- Proteome Biochemistry, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
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Ryan F, Zarruk JG, Lößlein L, David S. Ceruloplasmin Plays a Neuroprotective Role in Cerebral Ischemia. Front Neurosci 2019; 12:988. [PMID: 30670944 PMCID: PMC6331473 DOI: 10.3389/fnins.2018.00988] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 12/10/2018] [Indexed: 12/21/2022] Open
Abstract
Ceruloplasmin (Cp) is a ferroxidase that also plays a role in iron efflux from cells. It can thus help to regulate cellular iron homeostasis. In the CNS, Cp is expressed as a membrane-anchored form by astrocytes. Here, we assessed the role of Cp in permanent middle cerebral artery occlusion (pMCAO) comparing wildtype and Cp null mice. Our studies show that the lesion size is larger and functional recovery impaired in Cp null mice compared to wildtype mice. Expression of Cp increased ninefold at 72 h after pMCAO and remained elevated about twofold at day 14. We also assessed changes in mRNA and protein expression of molecules involved in iron homeostasis. As expected there was a reduction in ferroportin in Cp null mice at 72 h. There was also a remarkable increase in DMT1 protein in both genotypes at 72 h, being much higher in wildtype mice (19.5-fold), that then remained elevated about twofold at 14 days. No difference was seen in transferrin receptor 1 (TfR1) expression, except a small reduction in wildtype mice at 72 h, suggesting that the increase in DMT1 may underlie iron uptake independent of TfR1-endosomal uptake. There was also an increase of ferritin light chain in both genotypes. Iron histochemistry showed increased iron accumulation after pMCAO, initially along the lesion border and later throughout the lesion. Immunofluorescence labeling for ferritin (a surrogate marker for iron) and GFAP or CD11b showed increased ferritin in GFAP+ astrocytes along the lesion border in Cp null mice, while CD11b+ macrophages expressed ferritin equally in both genotypes. Increased lipid peroxidation assessed by 4HNE staining was increased threefold in Cp null mice at 72 h after pMCAO; and 3-nitrotyrosine labeling showed a similar trend. Three key pro-inflammatory cytokines (IL-1β, TNFα, and IL-6) were markedly increased at 24 h after pMCAO equally in both genotypes, and remained elevated at lower levels later, indicating that the lack of Cp does not alter key inflammatory cytokine expression after pMCAO. These data indicate that Cp expression is rapidly upregulated after pMCAO, and loss of Cp results in dysregulation of iron homeostasis, increased oxidative damage, greater lesion size and impaired recovery of function.
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Affiliation(s)
- Fari Ryan
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Juan G Zarruk
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Lena Lößlein
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Samuel David
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
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Das S, Sahoo PK. Ceruloplasmin, a moonlighting protein in fish. FISH & SHELLFISH IMMUNOLOGY 2018; 82:460-468. [PMID: 30144565 DOI: 10.1016/j.fsi.2018.08.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 08/15/2018] [Accepted: 08/21/2018] [Indexed: 06/08/2023]
Abstract
Ceruloplasmin is an ancient multicopper oxidase evolved to insure a safe handling of oxygen in some metabolic pathways of vertebrates. The current knowledge of its structure provides a glimpse of its plasticity, revealing a multitude of binding sites that point to an elaborate mechanism of multifunctional activity. Ceruloplasmin is highly conserved throughout the vertebrate evolution. Cupredoxin, a multi-cupper blue protein is believed to be the evolutionary precursor of ceruloplasmin with three trinuclear and three mononuclear copper binding sites. There are 20 copper-binding residues in ceruloplasmin gene out of which 16 residues are conserved in fish. This ceruloplasmin gene is being characterized in zebrafish (Danio rerio), rohu (Labeo rohita), Indian medaka (Oryzias melastigama), catfish (Ictalurus punctatus), icefish (Chionodraco rastrospinosus), goldfish (Carassius auratus) and yellow perch (Perca flaviscens). The complete coding sequence of fish ceruloplasmin gene is around 3.2 kb which codes for 1000 to 1100 amino acid residues. The size of ceruloplasmin gene sequence in fish ranges around 13 kb containing 20 exons and 19 introns. Liver is the major site of synthesis in fish. Increased expression of this gene during bacterial infection in channel catfish and rohu suggested its potential involvement in bacterial disease response in fish. It has been found to serve as an indirect marker for selection against Aeromonas hydrophila resistance in rohu carp. Ceruloplasmin expression is also evident during parasitic infection in few fish species. The role of this gene is well studied during inflammatory response to hormonal, drug and heavy metal mediated toxicity in fish. Overall, ceruloplasmin represents an example of a 'moonlighting' protein that overcomes the one gene-one structure-one function concept to follow the changes of the organism in its physiological and pathological conditions.
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Affiliation(s)
- Sweta Das
- Peninsular and Marine Fish Genetic Resources Centre, ICAR-National Bureau of Fish Genetic Resources, CMFRI Campus, Kochi 682 018, India
| | - Pramoda Kumar Sahoo
- ICAR-Central Institute of Freshwater Aquaculture, Kausalyaganga, Bhubaneswar 751 002, India.
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Ducharme P, Zarruk JG, David S, Paquin J. The ferroxidase ceruloplasmin influences Reelin processing, cofilin phosphorylation and neuronal organization in the developing brain. Mol Cell Neurosci 2018; 92:104-113. [PMID: 30077770 DOI: 10.1016/j.mcn.2018.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 07/10/2018] [Accepted: 07/30/2018] [Indexed: 12/09/2022] Open
Abstract
Ceruloplasmin (Cp) is an important extracellular regulator of iron metabolism. We showed previously that it stimulates Reelin proteolytic processing and cell aggregation in cultures of developing neurons. Reelin is a secreted protein required for the correct positioning of neurons in the brain. It is cleaved in vivo into N-terminally-derived 300K and 180K fragments through incompletely known mechanisms. One of Reelin signaling targets is the actin-binding protein cofilin, the phosphorylation of which is diminished in Reelin-deficient mice. This work looked for in vivo evidence of a relationship between Cp, Reelin and neuronal organization during brain development by analyzing wild-type and Cp-null mice. Cp as well as the full-length, 300K and 180K Reelin species appeared together in wild-type brains at embryonic day (E) 12.5 by immunoblotting. In wild-type compared to Cp-null brains, there was more 300K Reelin from E12.5 to E17.5, a period characterized by extensive, radially directed neuronal migration in the cerebral cortex. Immunofluorescence labeling of tissue sections at E16.5 revealed the localization of Cp with radial glia and meningeal cells adjacent to Reelin-producing Cajal-Retzius neurons, underlining the proximity of Cp and Reelin. Cofilin phosphorylation was seen starting at E10.5-E12.5 and lasted longer until postnatal day 7 in wild-type than Cp-null mice. Finally, using CUX1 as a marker revealed defective accumulation of neurons in layers II/III in neonatal and adult Cp-null mice. These results combined with our earlier work point to a potentially new role of Cp in Reelin processing and signaling and neuronal organization in the cerebral cortex in vivo.
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Affiliation(s)
- Philippe Ducharme
- Département de Chimie and Centre BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, Quebec H3C 3P8, Canada.
| | - Juan G Zarruk
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada.
| | - Samuel David
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada.
| | - Joanne Paquin
- Département de Chimie and Centre BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, Quebec H3C 3P8, Canada.
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Wu Y, Shen L, Wang R, Tang J, Ding SQ, Wang SN, Guo XY, Hu JG, Lü HZ. Increased ceruloplasmin expression caused by infiltrated leukocytes, activated microglia, and astrocytes in injured female rat spinal cords. J Neurosci Res 2018; 96:1265-1276. [PMID: 29377294 DOI: 10.1002/jnr.24221] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/21/2017] [Accepted: 01/11/2018] [Indexed: 12/17/2022]
Abstract
Ceruloplasmin (Cp), an enzyme containing six copper atoms, has important roles in iron homeostasis and antioxidant defense. After spinal cord injury (SCI), the cellular components in the local microenvironment are very complex and include functional changes of resident cells and the infiltration of leukocytes. It has been confirmed that Cp is elevated primarily in astrocytes and to a lesser extent in macrophages following SCI in mice. However, its expression in other cell types is still not very clear. In this manuscript, we provide a sensible extension of these findings by examining this system within a female Sprague-Dawley rat model and expanding the scope of inquiry to include additional cell types. Quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that the Cp mRNA and protein in SCI tissue homogenates were quite consistent with prior publications. However, we observed that Cp was expressed not only in GFAP+ astrocytes (consistent with prior reports) but also in CD11b+ microglia, CNPase+ oligodendrocytes, NeuN+ neurons, CD45+ leukocytes, and CD68+ activated microglia/macrophages. Quantitative analysis proved that infiltrated leukocytes, activated microglia/macrophages, and astrocytes should be the major sources of increased Cp.
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Affiliation(s)
- Yan Wu
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Lin Shen
- Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - Rui Wang
- Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - Jie Tang
- Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Shu-Qin Ding
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - Sai-Nan Wang
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Xue-Yan Guo
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Jian-Guo Hu
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - He-Zuo Lü
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
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10
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Platonova NA, Orlov IA, Klotchenko SA, Babich VS, Ilyechova EY, Babich PS, Garmai YP, Vasin AV, Tsymbalenko NV, Puchkova LV. Ceruloplasmin gene expression profile changes in the rat mammary gland during pregnancy, lactation and involution. J Trace Elem Med Biol 2017; 43:126-134. [PMID: 28089327 DOI: 10.1016/j.jtemb.2016.12.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 10/31/2016] [Accepted: 12/31/2016] [Indexed: 11/19/2022]
Abstract
Copper metabolism disturbances in mammary gland (MG) cells have severe consequences in newborns. The mechanism that controls the balance of copper in the MG has not been thoroughly characterized. Four primary copper homeostasis genes in mammals: (1) ceruloplasmin (Cp) encoding multifunction multicopper blue (ferr)oxidase; (2) CTR1 encoding high affinity copper importer 1; and (3 and 4) two similar genes encoding Cu(I)/Cu(II)-ATPases P1 type (ATP7A and ATP7B) responsible for copper efflux from the cells and metallation of cuproenzymes formed in the Golgi complex are expressed in MG. This study aimed to characterize expression of these genes during pregnancy, lactation and forced involution in the rat MG. We found that Cp anchored to the plasma membrane and ATP7A were expressed during pregnancy and lactation. Soluble Cp and ATP7B were highly expressed in lactating MG decreasing to its ending. CTR1 activity increased during MG growth and reached its maximum at postpartum and then it decreased until the end of lactation. During early forced MG involution, Cp gene expression persisted; while a form of Cp that lacked exon 18 appeared. We suggest that Cp gene expressional changes at the transcriptional and posttranscriptional level reflect various physiological functions of Cp proteins during MG remodeling.
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Affiliation(s)
- Natalia A Platonova
- Institute of Experimental Medicine, Pavlova str., 12, St., Petersburg 197376, Russia
| | - Iurii A Orlov
- ITMO University, Kronverksky av., 49, St., Petersburg 197101, Russia; Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya str., 29, St., Petersburg 195251, Russia.
| | - Sergey A Klotchenko
- Institute of Experimental Medicine, Pavlova str., 12, St., Petersburg 197376, Russia
| | - Victor S Babich
- School of Liberal Arts and Sciences, Mercy College of Health Sciences, Des Moines, IA, USA
| | - Ekaterina Y Ilyechova
- Institute of Experimental Medicine, Pavlova str., 12, St., Petersburg 197376, Russia; ITMO University, Kronverksky av., 49, St., Petersburg 197101, Russia
| | - Polina S Babich
- Institute of Experimental Medicine, Pavlova str., 12, St., Petersburg 197376, Russia
| | - Yuri P Garmai
- Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya str., 29, St., Petersburg 195251, Russia
| | - Andrey V Vasin
- Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya str., 29, St., Petersburg 195251, Russia
| | - Nadezhda V Tsymbalenko
- Institute of Experimental Medicine, Pavlova str., 12, St., Petersburg 197376, Russia; ITMO University, Kronverksky av., 49, St., Petersburg 197101, Russia
| | - Liudmila V Puchkova
- Institute of Experimental Medicine, Pavlova str., 12, St., Petersburg 197376, Russia; ITMO University, Kronverksky av., 49, St., Petersburg 197101, Russia; Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya str., 29, St., Petersburg 195251, Russia
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11
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Di Bella LM, Alampi R, Biundo F, Toscano G, Felice MR. Copper chelation and interleukin-6 proinflammatory cytokine effects on expression of different proteins involved in iron metabolism in HepG2 cell line. BMC BIOCHEMISTRY 2017; 18:1. [PMID: 28118841 PMCID: PMC5259844 DOI: 10.1186/s12858-017-0076-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 01/09/2017] [Indexed: 12/21/2022]
Abstract
Background In vertebrates, there is an intimate relationship between copper and iron homeostasis. Copper deficiency, which leads to a defect in ceruloplasmin enzymatic activity, has a strong effect on iron homeostasis resulting in cellular iron retention. Much is known about the mechanisms underlying cellular iron retention under “normal” conditions, however, less is known about the effect of copper deficiency during inflammation. Results We show that copper deficiency and the inflammatory cytokine interleukin-6 have different effects on the expression of proteins involved in iron and copper metabolism such as the soluble and glycosylphosphtidylinositol anchored forms of ceruloplasmin, hepcidin, ferroportin1, transferrin receptor1, divalent metal transporter1 and H-ferritin subunit. We demonstrate, using the human HepG2 cell line, that in addition to ceruloplasmin isoforms, copper deficiency affects other proteins, some posttranslationally and some at the transcriptional level. The addition of interleukin-6, moreover, has different effects on expression of ferroportin1 and ceruloplasmin, in which ferroportin1 is decreased while ceruloplasmin is increased. These effects are stronger when a copper chelating agent and IL-6 are used simultaneously. Conclusions These results suggest that copper chelation has effects not only on ceruloplasmin but also on other proteins involved in iron metabolism, sometimes at the mRNA level and, in inflammatory conditions, the functions of ferroportin and ceruloplasmin may be independent.
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Affiliation(s)
- Luca Marco Di Bella
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166, Messina, Italy.,Inter University National Group of Marine Sciences (CoNISMa), Piazzale Flaminio, 9, 00196, Rome, Italy
| | - Roberto Alampi
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Flavia Biundo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Giovanni Toscano
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Maria Rosa Felice
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166, Messina, Italy.
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12
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Linder MC. Ceruloplasmin and other copper binding components of blood plasma and their functions: an update. Metallomics 2016; 8:887-905. [PMID: 27426697 DOI: 10.1039/c6mt00103c] [Citation(s) in RCA: 195] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
We know that blood plasma contains many proteins and also other components that bind copper. The largest contributor to copper in the plasma is ceruloplasmin, which accounts for 40-70 percent. Apart from ceruloplasmin and albumin, most of these components have not been studied extensively, and even for ceruloplasmin and albumin, much remains to be discovered. New components with new functions, and new functions of known components are emerging, some warranting reconsideration of earlier findings. The author's laboratory has been actively involved in research on this topic. This review summarizes and updates our knowledge of the nature and functions of ceruloplasmin and the other known and emerging copper-containing molecules (principally proteins) in this fluid, to better understand how they contribute to copper homeostasis and consider their potential significance to health and disease.
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Affiliation(s)
- M C Linder
- California State University, Fullerton, CA, USA.
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13
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Wang J, Bi M, Xie J. Ceruloplasmin is Involved in the Nigral Iron Accumulation of 6-OHDA-Lesioned Rats. Cell Mol Neurobiol 2015; 35:661-8. [PMID: 25656940 PMCID: PMC11486195 DOI: 10.1007/s10571-015-0161-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Accepted: 01/30/2015] [Indexed: 12/14/2022]
Abstract
Elevated iron levels in the substantia nigra (SN) participate in neuronal death in Parkinson's disease (PD), while the mechanisms underlying the increased iron are still unknown. Ceruloplasmin (CP), a ferroxidase, converts highly toxic ferrous iron to its non-toxic ferric form, which cooperated with ferroportin1 (FP1) facilitating the export of iron from cells. To elucidate if the abnormal expression of CP is involved in the nigral iron accumulation, here, we investigated CP expression in the SN of rats lesioned by 6-hydroxydopamine (6-OHDA). We showed that FP1 and CP colocalized in the rat SN. One day after 6-OHDA lesion, when there was a half reduction in the number of dopaminergic neurons, the iron level was increased compared with the normal rats; both the mRNA and protein expressions of CP decreased compared with the control. When rats began showing rotation behavior induced by apomorphine, usually after 6 weeks since 6-OHDA lesion, they are considered PD models. In these PD models, almost no dopaminergic neurons can be detected in the lesioned SN and nigral iron level was further increased. At this time point, a further decrease of CP was observed. These results show that FP1 and CP colocalize in the rat brain, indicating the coordinated actions of the two proteins in the cellular iron export, and suggest that decreased expression of CP in the SN is involved in the nigral iron accumulation of 6-OHDA-lesioned rats.
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Affiliation(s)
- Jun Wang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071 China
| | - Mingxia Bi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071 China
| | - Junxia Xie
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, 266071 China
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14
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Conti A, Alessio M. Comparative Proteomics for the Evaluation of Protein Expression and Modifications in Neurodegenerative Diseases. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2015; 121:117-52. [PMID: 26315764 DOI: 10.1016/bs.irn.2015.05.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Together with hypothesis-driven approaches, high-throughput differential proteomic analysis performed primarily not only in human cerebrospinal fluid and serum but also on protein content of other tissues (blood cells, muscles, peripheral nerves, etc.) has been used in the last years to investigate neurodegenerative diseases. Even if the goal for these analyses was mainly the discovery of neurodegenerative disorders biomarkers, the characterization of specific posttranslational modifications (PTMs) and the differential protein expression resulted in being very informative to better define the pathological mechanisms. In this chapter are presented and discussed the positive aspects and challenges of the outcomes of some of our investigations on neurological and neurodegenerative disease, in order to highlight the important role of protein PTMs studies in proteomics-based approaches.
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Affiliation(s)
- Antonio Conti
- Proteome Biochemistry, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Massimo Alessio
- Proteome Biochemistry, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
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15
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Jiang R, Hua C, Wan Y, Jiang B, Hu H, Zheng J, Fuqua BK, Dunaief JL, Anderson GJ, David S, Vulpe CD, Chen H. Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain. J Nutr 2015; 145:1003-9. [PMID: 25788583 DOI: 10.3945/jn.114.207316] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 02/18/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Iron accumulation in the central nervous system (CNS) is a common feature of many neurodegenerative diseases. Multicopper ferroxidases (MCFs) play an important role in cellular iron metabolism. However, the role of MCFs in the CNS in health and disease remains poorly characterized. OBJECTIVE The aim was to study the role of hephaestin (HEPH) and ceruloplasmin (CP) in CNS iron metabolism and homeostasis. METHODS Iron concentrations and L-ferritin protein levels of selected brain regions were determined in global hephaestin knockout (Heph KO), global ceruloplasmin knockout (Cp KO), and wild-type (WT) male mice at 6-7 mo of age. Gene expression of divalent metal transporter 1 (Dmt1), ferroportin 1 (Fpn1), Heph, Cp, and transferrin receptor 1 (Tfrc) and HEPH protein level was quantitated in the same brain regions. RESULTS Iron and L-ferritin protein levels were significantly increased in Heph KO mouse brain cortex (iron: 30%, P < 0.05; L-ferritin: 200%, P < 0.05), hippocampus (iron: 80%, P < 0.05; L-ferritin: 300%, P < 0.05), brainstem (iron: 20%, P < 0.05; L-ferritin: 150%, P < 0.05), and cerebellum (iron: 20%, P < 0.05; L-ferritin: 100%, P < 0.05) regions than in WT and Cp KO mouse brain regions at 6 mo of age. Expression of the Heph gene was significantly increased in the Cp KO mouse cortex (100%; P < 0.01), hippocampus (350%; P < 0.001), brainstem (30%; P < 0.01), and cerebellum (150%; P < 0.001) than in WT controls, and Cp gene expression was significantly decreased in the Heph KO mouse hippocampus (20%; P < 0.05) than in WT control mice at 6 mo of age. CONCLUSIONS Ablation of HEPH or CP results in disordered brain iron homeostasis in mice. Heph KO may provide a novel model for neurodegenerative disorders.
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Affiliation(s)
- Ruiwei Jiang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Chao Hua
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Yike Wan
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Bo Jiang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Huiyin Hu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Jiashuo Zheng
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Brie K Fuqua
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA; Berghofer Medical Research Institute, Brisbane, Australia
| | - Joshua L Dunaief
- F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA; and
| | | | - Samuel David
- Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Canada
| | - Chris D Vulpe
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA
| | - Huijun Chen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
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16
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Zarruk JG, Berard JL, Passos dos Santos R, Kroner A, Lee J, Arosio P, David S. Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation. Neurobiol Dis 2015; 81:93-107. [PMID: 25724358 DOI: 10.1016/j.nbd.2015.02.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Revised: 01/16/2015] [Accepted: 02/03/2015] [Indexed: 02/06/2023] Open
Abstract
Iron accumulation occurs in the CNS in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying such iron accumulation are not fully understood. We studied the expression and cellular localization of molecules involved in cellular iron influx, storage, and efflux. This was assessed in two mouse models of EAE: relapsing-remitting (RR-EAE) and chronic (CH-EAE). The expression of molecules involved in iron homeostasis was assessed at the onset, peak, remission/progressive and late stages of the disease. We provide several lines of evidence for iron accumulation in the EAE spinal cord which increases with disease progression and duration, is worse in CH-EAE, and is localized in macrophages and microglia. We also provide evidence that there is a disruption of the iron efflux mechanism in macrophages/microglia that underlie the iron accumulation seen in these cells. Macrophages/microglia also lack expression of the ferroxidases (ceruloplasmin and hephaestin) which have antioxidant effects. In contrast, astrocytes which do not accumulate iron, show robust expression of several iron influx and efflux proteins and the ferroxidase ceruloplasmin which detoxifies ferrous iron. Astrocytes therefore are capable of efficiently recycling iron from sites of EAE lesions likely into the circulation. We also provide evidence of marked dysregulation of mitochondrial function and energy metabolism genes, as well as of NADPH oxidase genes in the EAE spinal cord. This data provides the basis for the selective iron accumulation in macrophage/microglia and further evidence of severe mitochondrial dysfunction in EAE. It may provide insights into processes underling iron accumulation in MS and other neurodegenerative diseases in which iron accumulation occurs.
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Affiliation(s)
- Juan G Zarruk
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada
| | - Jennifer L Berard
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada
| | - Rosmarini Passos dos Santos
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada
| | - Antje Kroner
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada
| | - Jaekwon Lee
- Dept of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, N210 Beadle Center, Lincoln, NE 68588-0664 USA
| | - Paolo Arosio
- Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Samuel David
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada.
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17
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Ceruloplasmin potentiates nitric oxide synthase activity and cytokine secretion in activated microglia. J Neuroinflammation 2014; 11:164. [PMID: 25224679 PMCID: PMC4174266 DOI: 10.1186/s12974-014-0164-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 09/04/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ceruloplasmin is a ferroxidase expressed in the central nervous system both as soluble form in the cerebrospinal fluid (CSF) and as membrane-bound GPI-anchored isoform on astrocytes, where it plays a role in iron homeostasis and antioxidant defense. It has been proposed that ceruloplasmin is also able to activate microglial cells with ensuing nitric oxide (NO) production, thereby contributing to neuroinflammatory conditions. In light of the possible role of ceruloplasmin in neurodegenerative diseases, we were prompted to investigate how this protein could contribute to microglial activation in either its native form, as well as in its oxidized form, recently found generated in the CSF of patients with Parkinson's and Alzheimer's diseases. METHODS Primary rat microglial-enriched cultures were treated with either ceruloplasmin or oxidized-ceruloplasmin, alone or in combination with lipopolysaccharide (LPS). Production of NO and expression of inducible nitric oxide synthase (iNOS) were evaluated by Griess assay and Western blot analysis, respectively. The productions of the pro-inflammatory cytokine IL-6 and the chemokine MIP-1α were assessed by quantitative RT-PCR and ELISA. RESULTS Regardless of its oxidative status, ceruloplasmin by itself was not able to activate primary rat microglia. However, ceruloplasmin reinforced the LPS-induced microglial activation, promoting an increase of NO production, as well as the induction of IL-6 and MIP-1α. Interestingly, the ceruloplasmin-mediated effects were observed in the absence of an additional induction of iNOS expression. The evaluation of iNOS activity in primary glial cultures and in vitro suggested that the increased NO production induced by the combined LPS and ceruloplasmin treatment is mediated by a potentiation of the enzymatic activity. CONCLUSIONS Ceruloplasmin potentiates iNOS activity in microglial cells activated by a pro-inflammatory stimulus, without affecting iNOS expression levels. This action might be mediated by the activation of a yet unknown Cp receptor that triggers intracellular signaling that cross-talks with the response elicited by LPS or other pro-inflammatory stimuli. Therefore, ceruloplasmin might contribute to pathological conditions in the central nervous system by exacerbating neuroinflammation.
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18
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Musci G, Polticelli F, Bonaccorsi di Patti MC. Ceruloplasmin-ferroportin system of iron traffic in vertebrates. World J Biol Chem 2014; 5:204-215. [PMID: 24921009 PMCID: PMC4050113 DOI: 10.4331/wjbc.v5.i2.204] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 02/19/2014] [Indexed: 02/05/2023] Open
Abstract
Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin (SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasmin-ferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.
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19
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Abstract
Aceruloplasminemia is an inherited neurodegenerative disorder involving "neurodegeneration with brain iron accumulation," which is caused by genetic defects in the ceruloplasmin gene. Ceruloplasmin is a multicopper oxidase with ferroxidase activity that oxidizes ferrous iron following its transfer to extracellular transferrin. In the central nervous system, a glycosylphosphatidylinositol-linked ceruloplasmin bound to the cell membranes was found to be the major isoform of this protein. Aceruloplasminemia is characterized by diabetes, retinal degeneration, and progressive neurological symptoms, including extrapyramidal symptoms, ataxia, and dementia. Clinical and pathological studies and investigations of cell culture and murine models revealed that there is an iron-mediated cellular radical injury caused by a marked accumulation of iron in the affected parenchymal tissues. The aim of this chapter is to provide an overview of not only the clinical features, genetic and molecular pathogenesis, and treatment of aceruloplasminemia but also the biological and physiological features of iron metabolism.
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Affiliation(s)
- Satoshi Kono
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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20
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Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention. J Neurosci 2012; 31:18568-77. [PMID: 22171055 DOI: 10.1523/jneurosci.3768-11.2011] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.
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21
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Mostad EJ, Prohaska JR. Glycosylphosphatidylinositol-linked ceruloplasmin is expressed in multiple rodent organs and is lower following dietary copper deficiency. Exp Biol Med (Maywood) 2011; 236:298-308. [DOI: 10.1258/ebm.2010.010256] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Ceruloplasmin (Cp), a multicopper ferroxidase, is expressed as both a secreted (sCp) plasma enzyme from the liver and a membrane-bound glycosylphosphatidylinositol-anchored (GPI-Cp) splice variant protein. Cp is thought to be essential for iron mobilization as selective iron overload occurs in aceruloplasminemia in humans and in Cp null mice. Dietary copper-deficient (CuD) rodents have near total loss of Cp activity, severe loss of Cp protein and develop anemia. Hepatic iron augmentation is often observed, suggesting that loss of Cp function may be correlated with anemia. The impact of CuD treatment on GPI-Cp has not previously been evaluated. Our hypothesis was that CuD rodents would have lower levels of GPI-Cp and this would correlate with higher tissue iron retention. In these studies, GPI-Cp was detected in purified membranes of multiple organs of rats and mice but not Cp −/− mice. Immunoreactive Cp protein was released with phosphatidylinositol phospholipase C treatment and expressed ferroxidase activity. Following perinatal and postnatal copper restriction, GPI-Cp was markedly lower in the spleen and modestly lower in the liver of CuD rats and mice, when compared with copper-adequate (CuA) rodents. However, spleen non-heme iron (NHI) was lower in CuD than CuA rats, and not different in CuD mice. Hepatic iron was higher only in CuD mice. Spleen and liver membranes of CuD rats expressed augmented levels of ferroportin, the iron efflux transporter, which may explain lower NHI content in the spleen of CuD rats despite a greater than 50% lower level of the multicopper ferroxidase GPI-Cp. Spleen and liver levels of GPI-Cp mRNA were not impacted in CuD rats, suggesting that turnover rather than biosynthesis may explain the lower steady-state levels of GPI-Cp following dietary copper restriction. Lower GPI-Cp did not correlate with tissue iron retention and thus the role, if any, of Cp in anemia of copper deficiency is unknown.
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Affiliation(s)
- Elise J Mostad
- Department of Biochemistry and Molecular Biology, University of Minnesota Medical School Duluth, Duluth, MN 55812, USA
| | - Joseph R Prohaska
- Department of Biochemistry and Molecular Biology, University of Minnesota Medical School Duluth, Duluth, MN 55812, USA
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22
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Abstract
Wilson's disease is a severe human disorder of copper homoeostasis. The disease is associated with various mutations in the ATP7B gene that encodes a copper-transporting ATPase, and a massive accumulation of copper in the liver and several other tissues. The most frequent disease manifestations include a wide spectrum of liver pathologies as well as neurological and psychiatric abnormalities. A combination of copper chelators and zinc therapy has been used to prevent disease progression; however, accurate and timely diagnosis of the disease remains challenging. Similarly, side effects of treatments are common. To understand better the biochemical and cellular basis of Wilson's disease, several animal models have been developed. This review focuses on genetically engineered Atp7b(-/-) mice and describes the properties of these knockout animals, insights into the disease progression generated using Atp7b(-/-) mice, as well as advantages and limitations of Atp7b(-/-) mice as an experimental model for Wilson's disease.
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Conti A, Iannaccone S, Sferrazza B, De Monte L, Cappa S, Franciotta D, Olivieri S, Alessio M. Differential expression of ceruloplasmin isoforms in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Proteomics Clin Appl 2008; 2:1628-37. [PMID: 21136813 DOI: 10.1002/prca.200780081] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Indexed: 11/08/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) a fatal degenerative disease that selectively affects motor neurons, likely results from a complex interplay among oxidative injury, excitotoxic stimulation, protein aggregation and genetic factors. Ceruloplasmin (Cp) protein is a ferroxidase that oxidizes toxic ferrous iron to its nontoxic ferric form, protecting the central nervous system (CNS) from iron deposition. Cp is thus considered as one of the main systems dedicated to the protection of the CNS from oxidative stress damage. We investigated Cp protein behaviour in the cerebrospinal fluid (CSF) of ALS patients of recent onset. An increased expression of Cp was observed in ALS (n = 16) compared to two control groups (healthy subjects, n = 11 and peripheral neuropathy patients, n = 10). 2-DE analysis revealed a differential expression of Cp isoforms in ALS patients compared to controls. ALS samples showed an increase in the relative abundance of more basic Cp forms, corresponding to the nonsialylated proteins. Despite the increase in protein expression, ferroxidase activity evaluated in the CSF of ALS patients was comparable to that of the controls, indicating a Cp functional impairment. Ceruloplasmin isoforms profile may be proposed as disease feature that could provide insight into the molecular mechanisms of ALS pathogenesis.
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Affiliation(s)
- Antonio Conti
- Proteome Biochemistry, San Raffaele Scientific Institute, Milan, Italy
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24
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Banha J, Marques L, Oliveira R, Martins MDF, Paixão E, Pereira D, Malhó R, Penque D, Costa L. Ceruloplasmin expression by human peripheral blood lymphocytes: a new link between immunity and iron metabolism. Free Radic Biol Med 2008; 44:483-92. [PMID: 17991445 DOI: 10.1016/j.freeradbiomed.2007.10.032] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Revised: 09/24/2007] [Accepted: 10/11/2007] [Indexed: 11/19/2022]
Abstract
Ceruloplasmin (CP) is a multicopper oxidase involved in the acute phase reaction to stress. Although the physiological role of CP is uncertain, its role in iron (Fe) homeostasis and protection against free radical-initiated cell injury has been widely documented. Previous studies showed the existence of two molecular isoforms of CP: secreted CP (sCP) and a membrane glycosylphosphatidylinositol (GPI)-anchored form of CP (GPI-CP). sCP is produced mainly by the liver and is abundant in human serum whereas GPI-CP is expressed in mammalian astrocytes, rat leptomeningeal cells, and Sertolli cells. Herein, we show using RT-PCR that human peripheral blood lymphocytes (huPBL) constitutively express the transcripts for both CP molecular isoforms previously reported. Also, expression of CP in huPBL is demonstrated by immunofluorescence with confocal microscopy and flow cytometry analysis using cells isolated from healthy blood donors with normal Fe status. Importantly, the results obtained show that natural killer cells have a significantly higher CP expression compared to all other major lymphocyte subsets. In this context, the involvement of lymphocyte-derived CP on host defense processes via its anti/prooxidant properties is proposed, giving further support for a close functional interaction between the immune system and the Fe metabolism.
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Affiliation(s)
- João Banha
- Instituto Nacional de Saúde Dr. Ricardo Jorge, IP (INSA), Lisboa, Portugal
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25
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Samsonov SA, Platonova NA, Skvortsov AN, Tsymbalenko NV, Vasin AV, Puchkova LV. Relationships between CTR1 activity and copper status in different rat organs. Mol Biol 2006. [DOI: 10.1134/s0026893306020051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. ACTA ACUST UNITED AC 2005; 49:633-40. [PMID: 16269323 DOI: 10.1016/j.brainresrev.2005.03.003] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2004] [Revised: 03/14/2005] [Accepted: 03/14/2005] [Indexed: 11/19/2022]
Abstract
For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.
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Chang YZ, Qian ZM, Wang K, Zhu L, Yang XD, Du JR, Jiang L, Ho KP, Wang Q, Ke Y. Effects of development and iron status on ceruloplasmin expression in rat brain. J Cell Physiol 2005; 204:623-31. [PMID: 15744747 DOI: 10.1002/jcp.20321] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The increased iron content in the brain of subjects with aceruloplasminemia has implicated ceruloplasmin (CP) as a major factor in the regulation of regional brain iron content. In this study, we investigated the effects of age and iron on CP expression in rat brain. In all four regions, the iron concentrations increased with developmental age. There is a similar trend in age-induced changes in CP mRNA and protein. The CP mRNA and protein levels were both lowest at postnatal day (PND) 7. The expression increased gradually with age, reaching the highest at PND196 in the striatum and substantia nigra, and at PND21 and PND63 in the cortex and hippocampus, respectively. This suggests the existence of an age-dependent pre-transcriptional regulation and a regionally specific effect of age on CP expression in the brain. Although total iron in all four regions was significantly lower in the rats fed with a low-iron diet for 6 weeks and higher in the rats with a high-iron diet than those in the control animals, no significant between-group differences in CP mRNA and protein were found in these animals, except in the substantia nigra where a significant increase in CP protein in high-iron rats was observed, and the reverse in low-iron rats. These findings suggested that the effects of iron on CP expression in the brain may be region-specific, and that regulation of CP expression by iron in the substantia nigra was at the post-transcriptional level.
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Affiliation(s)
- Yan Zhong Chang
- Laboratory of Brain Iron Metabolism, Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong
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28
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Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 2003; 278:27144-8. [PMID: 12743117 DOI: 10.1074/jbc.m301988200] [Citation(s) in RCA: 284] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Ceruloplasmin (Cp) is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form. A glycosylphosphatidylinositol (GPI)-anchored form of this enzyme is expressed by astrocytes in the mammalian central nervous system, whereas the secreted form is expressed by the liver and found in serum. Lack of this enzyme results in iron accumulation in the brain and neurodegeneration. Herein, we show using astrocytes purified from the central nervous system of Cp-null mice that GPI-Cp is essential for iron efflux and not involved in regulating iron influx. We also show that GPI-Cp colocalizes on the astrocyte cell surface with the divalent metal transporter IREG1 and is physically associated with IREG1. In addition, IREG1 alone is unable to efflux iron from astrocytes in the absence of GPI-Cp or secreted Cp. We also provide evidence that the divalent metal influx transporter DMT1 is expressed by astrocytes and is likely to mediate iron influx into these glial cells. The coordinated actions of GPI-Cp and IREG1 may be required for iron efflux from neural cells, and disruption of this balance could lead to iron accumulation in the central nervous system and neurodegeneration.
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Affiliation(s)
- Suh Young Jeong
- Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital Research Institute, Montreal, Quebec H3G 1A4, Canada
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