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Locatelli M, Farina C. Role of copper in central nervous system physiology and pathology. Neural Regen Res 2025; 20:1058-1068. [PMID: 38989937 PMCID: PMC11438321 DOI: 10.4103/nrr.nrr-d-24-00110] [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: 01/26/2024] [Revised: 03/21/2024] [Accepted: 04/23/2024] [Indexed: 07/12/2024] Open
Abstract
Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.
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Affiliation(s)
- Martina Locatelli
- Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Cinthia Farina
- Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
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2
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Gromadzka G, Wilkaniec A, Tarnacka B, Hadrian K, Bendykowska M, Przybyłkowski A, Litwin T. The Role of Glia in Wilson's Disease: Clinical, Neuroimaging, Neuropathological and Molecular Perspectives. Int J Mol Sci 2024; 25:7545. [PMID: 39062788 PMCID: PMC11276698 DOI: 10.3390/ijms25147545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/07/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Wilson's disease (WD) is inherited in an autosomal recessive manner and is caused by pathogenic variants of the ATP7B gene, which are responsible for impaired copper transport in the cell, inhibition of copper binding to apoceruloplasmin, and biliary excretion. This leads to the accumulation of copper in the tissues. Copper accumulation in the CNS leads to the neurological and psychiatric symptoms of WD. Abnormalities of copper metabolism in WD are associated with impaired iron metabolism. Both of these elements are redox active and may contribute to neuropathology. It has long been assumed that among parenchymal cells, astrocytes have the greatest impact on copper and iron homeostasis in the brain. Capillary endothelial cells are separated from the neuropil by astrocyte terminal legs, putting astrocytes in an ideal position to regulate the transport of iron and copper to other brain cells and protect them if metals breach the blood-brain barrier. Astrocytes are responsible for, among other things, maintaining extracellular ion homeostasis, modulating synaptic transmission and plasticity, obtaining metabolites, and protecting the brain against oxidative stress and toxins. However, excess copper and/or iron causes an increase in the number of astrocytes and their morphological changes observed in neuropathological studies, as well as a loss of the copper/iron storage function leading to macromolecule peroxidation and neuronal loss through apoptosis, autophagy, or cuproptosis/ferroptosis. The molecular mechanisms explaining the possible role of glia in copper- and iron-induced neurodegeneration in WD are largely understood from studies of neuropathology in Parkinson's disease and Alzheimer's disease. Understanding the mechanisms of glial involvement in neuroprotection/neurotoxicity is important for explaining the pathomechanisms of neuronal death in WD and, in the future, perhaps for developing more effective diagnostic/treatment methods.
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Affiliation(s)
- Grażyna Gromadzka
- Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Wóycickiego 1/3, 01-938 Warsaw, Poland
| | - Anna Wilkaniec
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego St., 02-106 Warsaw, Poland
| | - Beata Tarnacka
- Department of Rehabilitation, Medical University of Warsaw, Spartańska 1, 02-637 Warsaw, Poland
| | - Krzysztof Hadrian
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland (A.P.)
| | - Maria Bendykowska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis 5, 01-815 Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland (A.P.)
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
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Sluysmans S, Méan I, Xiao T, Boukhatemi A, Ferreira F, Jond L, Mutero A, Chang CJ, Citi S. PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis. Mol Biol Cell 2021; 32:ar34. [PMID: 34613798 PMCID: PMC8693958 DOI: 10.1091/mbc.e21-07-0355] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/24/2021] [Accepted: 09/28/2021] [Indexed: 01/12/2023] Open
Abstract
Copper homeostasis is crucial for cellular physiology and development, and its dysregulation leads to disease. The Menkes ATPase ATP7A plays a key role in copper efflux, by trafficking from the Golgi to the plasma membrane upon cell exposure to elevated copper, but the mechanisms that target ATP7A to the cell periphery are poorly understood. PDZD11 interacts with the C-terminus of ATP7A, which contains sequences involved in ATP7A trafficking, but the role of PDZD11 in ATP7A localization is unknown. Here we identify PLEKHA5 and PLEKHA6 as new interactors of PDZD11 that bind to the PDZD11 N-terminus through their WW domains similarly to the junctional protein PLEKHA7. Using CRISPR-KO kidney epithelial cells, we show by immunofluorescence microscopy that WW-PLEKHAs (PLEKHA5, PLEKHA6, PLEKHA7) recruit PDZD11 to distinct plasma membrane localizations and that they are required for the efficient anterograde targeting of ATP7A to the cell periphery in elevated copper conditions. Pull-down experiments show that WW-PLEKHAs promote PDZD11 interaction with the C-terminus of ATP7A. However, WW-PLEKHAs and PDZD11 are not necessary for ATP7A Golgi localization in basal copper, ATP7A copper-induced exit from the Golgi, and ATP7A retrograde trafficking to the Golgi. Finally, measuring bioavailable and total cellular copper, metallothionein-1 expression, and cell viability shows that WW-PLEKHAs and PDZD11 are required for maintaining low intracellular copper levels when cells are exposed to elevated copper. These data indicate that WW-PLEKHAs-PDZD11 complexes regulate the localization and function of ATP7A to promote copper extrusion in elevated copper.
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Affiliation(s)
- Sophie Sluysmans
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
| | - Isabelle Méan
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
| | - Tong Xiao
- Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
| | - Amina Boukhatemi
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
| | - Flavio Ferreira
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
| | - Lionel Jond
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
| | - Annick Mutero
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
| | - Christopher J. Chang
- Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720
| | - Sandra Citi
- Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland
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Haddad MR, Choi EY, Zerfas PM, Yi L, Martinelli D, Sullivan P, Goldstein DS, Centeno JA, Brinster LR, Ralle M, Kaler SG. Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev 2018; 10:165-178. [PMID: 30090842 PMCID: PMC6080355 DOI: 10.1016/j.omtm.2018.07.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 07/02/2018] [Indexed: 01/01/2023]
Abstract
Menkes disease is a lethal neurodegenerative disorder of copper metabolism caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Based on our prior clinical and animal studies, we seek to develop a therapeutic approach suitable for application in affected human subjects, using the mottled-brindled (mo-br) mouse model that closely mimics the Menkes disease biochemical and clinical phenotypes. Here, we evaluate the efficacy of low-, intermediate-, and high-dose recombinant adeno-associated virus serotype 9 (rAAV9)-ATP7A delivered to the cerebrospinal fluid (CSF), in combination with subcutaneous administration of clinical-grade copper histidinate (sc CuHis, IND #34,166). Mutant mice that received high-dose (1.6 × 1010 vg) cerebrospinal fluid-directed rAAV9-rsATP7A plus sc copper histidinate showed 53.3% long-term (≥300-day) survival compared to 0% without treatment or with either treatment alone. The high-dose rAAV9-rsATP7A plus sc copper histidinate-treated mutant mice showed increased brain copper levels, normalized brain neurochemical levels, improvement of brain mitochondrial abnormalities, and normal growth and neurobehavioral outcomes. This synergistic treatment effect represents the most successful rescue to date of the mo-br mouse model. Based on these findings, and the absence of a large animal model, we propose cerebrospinal fluid-directed rAAV9-rsATP7A gene therapy plus subcutaneous copper histidinate as a potential therapeutic approach to cure or ameliorate Menkes disease.
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Affiliation(s)
- Marie Reine Haddad
- Section on Translational Neuroscience, Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Eun-Young Choi
- Section on Translational Neuroscience, Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Patricia M. Zerfas
- Diagnostic and Research Services Branch, Office of Research Services, Bethesda, MD, USA
| | - Ling Yi
- Section on Translational Neuroscience, Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Diego Martinelli
- Section on Translational Neuroscience, Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Patricia Sullivan
- Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - David S. Goldstein
- Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Jose A. Centeno
- Division of Biology, Chemistry and Materials Science. Office of Science and Engineering Laboratories (OSEL), US Food and Drug Administration, Silver Spring, MD, USA
| | - Lauren R. Brinster
- Diagnostic and Research Services Branch, Office of Research Services, Bethesda, MD, USA
| | - Martina Ralle
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA
| | - Stephen G. Kaler
- Section on Translational Neuroscience, Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
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Ogórek M, Lenartowicz M, Starzyński R, Jończy A, Staroń R, Doniec A, Krzeptowski W, Bednarz A, Pierzchała O, Lipiński P, Rajfur Z, Baster Z, Gibas-Tybur P, Grzmil P. Atp7a and Atp7b regulate copper homeostasis in developing male germ cells in mice. Metallomics 2018; 9:1288-1303. [PMID: 28820536 DOI: 10.1039/c7mt00134g] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The maintenance of copper homeostasis is critical for all cells. As learned from mice with disturbed copper metabolism, this trace element is also important for spermatogenesis. The experiments conducted in yeasts have demonstrated that appropriate copper level must be preserved to enable meiosis progression; however, increased copper level is toxic for cells. This study aims to analyze the expression profile of Atp7a and Atp7b and other genes encoding copper-related proteins during spermatogenesis in mice. Using the transcripts and protein detection techniques, we demonstrate that within seminiferous tubuli, ATP7A is mainly present in early meiotic germ cells (leptotene to pachytene spermatocytes) and in Sertoli cells (SCs). During spermatogenesis, the progression Atp7a expression profile corresponds to Slc31a1 (encoding copper importer CTR1) and Atox1 (encoding chaperon protein, which delivers copper from CTR1 to ATP7A and ATP7B) expression, suggesting that male germ cells retrieve copper and ATP7A protects them from copper overdose. In contrast, ATP7B protein is observed in SCs and near elongated spermatids; thus, its function seems to be related to copper extraction during spermiogenesis. This is the first study to give a comprehensive view on the activity of copper-related genes during spermatogenesis in mice.
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Affiliation(s)
- Mateusz Ogórek
- Department of Genetics and Evolution, Institute of Zoology and Biomedical Research, Jagiellonian University Kraków, Gronostajowa 9, 30-387 Kraków, Poland.
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Affiliation(s)
- Karl Heinz Weiss
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg
| | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology (HMGU) and Institute of Toxicology and Environmental Hygiene (Technical University Munich), Munich, Germany
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Concilli M, Iacobacci S, Chesi G, Carissimo A, Polishchuk R. A systems biology approach reveals new endoplasmic reticulum-associated targets for the correction of the ATP7B mutant causing Wilson disease. Metallomics 2017; 8:920-930. [PMID: 27714068 DOI: 10.1039/c6mt00148c] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Copper (Cu) is an important trace element required for the activity of essential enzymes. However, excess Cu compromises the redox balance in cells and tissues causing serious toxicity. The process of disposal of excess Cu from organisms relies on the activity of Cu-transporting ATPase ATP7B. ATP7B is mainly expressed in liver hepatocytes where it sequesters the potentially toxic metal and mediates its excretion into the bile. Mutations in the ATP7B gene cause Wilson disease (WD), which is characterized by the accumulation of toxic Cu in the liver due to the scarce expression of ATP7B as well as the failure of ATP7B mutants to pump Cu and/or traffic to the Cu-excretion sites. The most frequent ATP7B mutant, H1069Q, still presents a significant Cu-transporting activity, but undergoes retention within the endoplasmic reticulum (ER) where the mutant is rapidly degraded. Expression of this ATP7B mutant has been recently reported to activate the p38 and JNK stress kinase pathways, which, in turn, trigger quality control mechanisms leading to the arrest of ATP7B-H1069Q in the ER and to the acceleration of its degradation. However, the main molecular players operating in these p38/JNK-dependent ER quality control pathways remain to be discovered. By using a combination of RNAseq, bioinformatics and RNAi approaches, we found a cluster of ER quality control genes whose expression is controlled by p38 and JNK and is required for the efficient retention of the ATP7B-H1069Q mutant in the ER. Silencing these genes reduced the accumulation of the ATP7B mutant in the ER and facilitated the mutant sorting and export to the Golgi and post-Golgi copper excretion sites. In sum, our findings reveal the ER-associated genes that could be utilized for the correction of ATP7B mutants and, hence, for the normalization of Cu homeostasis in Wilson disease.
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Affiliation(s)
- Mafalda Concilli
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, NA 80078, Italy.
| | - Simona Iacobacci
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, NA 80078, Italy.
| | - Giancarlo Chesi
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, NA 80078, Italy.
| | - Annamaria Carissimo
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, NA 80078, Italy.
| | - Roman Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, NA 80078, Italy.
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Kanthlal SK, Joseph J, Baskaran Pillai AK, Padma UD. Neural effects in copper deficient Menkes disease: ATP7A-a distinctive marker. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(16)61107-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Lenartowicz M, Krzeptowski W, Lipiński P, Grzmil P, Starzyński R, Pierzchała O, Møller LB. Mottled Mice and Non-Mammalian Models of Menkes Disease. Front Mol Neurosci 2015; 8:72. [PMID: 26732058 PMCID: PMC4684000 DOI: 10.3389/fnmol.2015.00072] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 11/06/2015] [Indexed: 12/27/2022] Open
Abstract
Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB). Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80%) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals.
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Affiliation(s)
- Małgorzata Lenartowicz
- Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University Kraków, Poland
| | - Wojciech Krzeptowski
- Department of Cell Biology and Imaging, Institute of Zoology, Jagiellonian University Kraków, Poland
| | - Paweł Lipiński
- Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences Wólka Kosowska, Poland
| | - Paweł Grzmil
- Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University Kraków, Poland
| | - Rafał Starzyński
- Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences Wólka Kosowska, Poland
| | - Olga Pierzchała
- Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University Kraków, Poland
| | - Lisbeth Birk Møller
- Applied Human Molecular Genetics, Kennedy Center, Rigshospitalet, Copenhagen University Hospital Glostrup, Denmark
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Ogra Y. Molecular mechanisms underlying copper homeostasis in Mammalian cells. Nihon Eiseigaku Zasshi 2015; 69:136-45. [PMID: 24858509 DOI: 10.1265/jjh.69.136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Copper (Cu) is an essential metal for living organisms that utilize oxygen for respiration and is required as a cofactor of redox-regulating enzymes, such as superoxide dismutase, ceruloplasmin, lysyl oxidase, tyrosinase, and dopamine β-hydroxylase. However, the redox-active property of this metal may have toxic effects on cells due to the generation of harmful reactive oxygen species. Given these circumstances, it is said that cells have a dependable system for Cu homeostasis that efficiently distributes this essential metal to cuproenzymes, thereby preventing damage to proteins, nucleic acids, sugars, and lipids. In particular, influx, efflux, and intracellular distribution with maintenance of the oxidation state of Cu are strictly regulated. Several groups of Cu-regulating factors have been identified in mammalian cells, i.e., Cu transporters, Cu chaperones, Cu-binding proteins/peptides, and others. In this review, the features of the Cu-regulating factors are concisely examined in terms of molecular mechanisms underlying Cu homeostasis in cells.
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Affiliation(s)
- Yasumitsu Ogra
- Laboratory of Chemical Toxicology and Environmental Health, Showa Pharmaceutical University
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Jain S, Farías GG, Bonifacino JS. Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1. Mol Biol Cell 2014; 26:218-28. [PMID: 25378584 PMCID: PMC4294670 DOI: 10.1091/mbc.e14-07-1177] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Recognition of dileucine signals by AP-1 mediates somatodendritic sorting of the copper transporter ATP7B and the SNARE VAMP4 in hippocampal neurons, establishing AP-1 as a global regulator of polarized sorting and contributing to the understanding of neuronal copper metabolism under physiological and pathological conditions. Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu2+ transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the σ1 subunit of the clathrin adaptor AP-1. Under basal Cu2+ conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative σ1 mutant resulted in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Furthermore, addition of high Cu2+ concentrations, previously shown to reduce ATP7B incorporation into AP-1–containing clathrin-coated vesicles, caused loss of TGN localization and somatodendritic polarity of ATP7B. These findings support the notion of AP-1 as an effector of polarized sorting in neurons and suggest that altered polarity of ATP7B in polarized cell types might contribute to abnormal copper metabolism in the MEDNIK syndrome, a neurocutaneous disorder caused by mutations in the σ1A subunit isoform of AP-1.
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Affiliation(s)
- Shweta Jain
- Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Ginny G Farías
- Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Juan S Bonifacino
- Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
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12
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Transendothelial Transport and Its Role in Therapeutics. INTERNATIONAL SCHOLARLY RESEARCH NOTICES 2014; 2014:309404. [PMID: 27355037 PMCID: PMC4897564 DOI: 10.1155/2014/309404] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/13/2014] [Accepted: 06/18/2014] [Indexed: 12/17/2022]
Abstract
Present review paper highlights role of BBB in endothelial transport of various substances into the brain. More specifically, permeability functions of BBB in transendothelial transport of various substances such as metabolic fuels, ethanol, amino acids, proteins, peptides, lipids, vitamins, neurotransmitters, monocarbxylic acids, gases, water, and minerals in the peripheral circulation and into the brain have been widely explained. In addition, roles of various receptors, ATP powered pumps, channels, and transporters in transport of vital molecules in maintenance of homeostasis and normal body functions have been described in detail. Major role of integral membrane proteins, carriers, or transporters in drug transport is highlighted. Both diffusion and carrier mediated transport mechanisms which facilitate molecular trafficking through transcellular route to maintain influx and outflux of important nutrients and metabolic substances are elucidated. Present review paper aims to emphasize role of important transport systems with their recent advancements in CNS protection mainly for providing a rapid clinical aid to patients. This review also suggests requirement of new well-designed therapeutic strategies mainly potential techniques, appropriate drug formulations, and new transport systems for quick, easy, and safe delivery of drugs across blood brain barrier to save the life of tumor and virus infected patients.
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Fu X, Zhang Y, Jiang W, Monnot AD, Bates CA, Zheng W. Regulation of copper transport crossing brain barrier systems by Cu-ATPases: effect of manganese exposure. Toxicol Sci 2014; 139:432-51. [PMID: 24614235 DOI: 10.1093/toxsci/kfu048] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced parkinsonian disorder. Studies by quantitative real-time RT-PCR (qPCR), Western blot, and immunocytochemistry revealed that both Cu-ATPases expressed abundantly in BBB and BCB. Transport kinetic studies by in situ brain infusion and ventriculo-cisternal (VC) perfusion in Sprague Dawley rat suggested that the BBB was a major site for Cu entry into brain, whereas the BCB was a predominant route for Cu efflux from the CSF to blood. Confocal evidence showed that the presence of excess Cu or Mn in the choroid plexus cells led to ATP7A relocating toward the apical microvilli facing the CSF, but ATP7B toward the basolateral membrane facing blood. Mn exposure inhibited the production of both Cu-ATPases. Collectively, these data suggest that Cu is transported by the BBB from the blood to brain, which is mediated by ATP7A in brain capillary. By diffusion, Cu ions move from the interstitial fluid into the CSF, where they are taken up by the BCB. Within the choroidal epithelial cells, Cu ions are transported by ATP7B back to the blood. Mn exposure alters these processes, leading to Cu dyshomeostasis-associated neuronal injury.
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Affiliation(s)
- Xue Fu
- School of Health Sciences, Purdue University, West Lafayette, Indiana 47907
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Telianidis J, Hung YH, Materia S, Fontaine SL. Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis. Front Aging Neurosci 2013; 5:44. [PMID: 23986700 PMCID: PMC3750203 DOI: 10.3389/fnagi.2013.00044] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 08/05/2013] [Indexed: 12/21/2022] Open
Abstract
Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.
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Affiliation(s)
- Jonathon Telianidis
- Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin UniversityBurwood, VIC, Australia
- Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin UniversityBurwood, VIC, Australia
| | - Ya Hui Hung
- Oxidation Biology Unit, Florey Institute of Neuroscience and Mental HealthParkville, VIC, Australia
- Centre for Neuroscience Research, The University of MelbourneParkville, VIC, Australia
| | - Stephanie Materia
- Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin UniversityBurwood, VIC, Australia
- Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin UniversityBurwood, VIC, Australia
| | - Sharon La Fontaine
- Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin UniversityBurwood, VIC, Australia
- Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin UniversityBurwood, VIC, Australia
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Parker SJ, Koistinaho J, White AR, Kanninen KM. Biometals in rare neurodegenerative disorders of childhood. Front Aging Neurosci 2013; 5:14. [PMID: 23531702 PMCID: PMC3607070 DOI: 10.3389/fnagi.2013.00014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 03/05/2013] [Indexed: 01/01/2023] Open
Abstract
Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.
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Affiliation(s)
- Sarah J Parker
- Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland Kuopio, Finland
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16
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Lee SM, Park KH, Kim SS, Kwon DW, Hong SC. Effect of the Mn oxidation state and lattice oxygen in Mn-based TiO2 catalysts on the low-temperature selective catalytic reduction of NO by NH3. JOURNAL OF THE AIR & WASTE MANAGEMENT ASSOCIATION (1995) 2012; 62:1085-1092. [PMID: 23019822 DOI: 10.1080/10962247.2012.696532] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
UNLABELLED TiO2-supported manganese oxide catalysts formed using different calcination temperatures were prepared by using the wet-impregnation method and were investigated for their activity in the low-temperature selective catalytic reduction (SCR) of NO by NH3 with respect to the Mn valence and lattice oxygen behavior. The surface and bulk properties of these catalysts were examined using Brunauer-Emmett-Teller (BET) surface area, X-ray diffraction (XRD), temperature-programmed reduction (TPR), and temperature-programmed desorption (TPD). Catalysts prepared using lower calcination temperatures, which contained Mn4+ displayed high SCR activity at low temperatures and possessed several acid sites and active oxygen. The TPD analysis determined that the Brönsted and Lewis acid sites in the Mn/TiO2 catalysts were important for the low-temperature SCR at 80-160 and 200-350 degrees C, respectively. In addition, the available lattice oxygen was important for attaining high NO to NO2 oxidation at low temperatures. IMPLICATIONS Recently, various Mn catalysts have been evaluated as SCR catalysts. However, there have been no studies on the relationship of adsorption and desorption properties and behavior of lattice oxygen according to the valence state for manganese oxides (MnO(x)). Therefore, in this study, the catalysts were prepared by the wet-impregnation method at different calcination temperatures in order to show the difference of manganese oxidation state. These catalysts were then characterized using various physicochemical techniques, including BET, XRD, TPR, and TPD, to understand the structure, oxidation state, redox properties, and adsorption and desorption properties of the Mn/TiO2 catalysts.
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Affiliation(s)
- Sang Moon Lee
- Department of Environmental Energy Systems Engineering, Kyonggi University, 94 San, Iui-dong, Youngtong-ku, Suwon-si, Gyeonggi-do 442-760, South Korea
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ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Mol Ther 2011; 19:2114-23. [PMID: 21878905 DOI: 10.1038/mt.2011.143] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57BL/6 background were not rescued by peripheral copper administration, and used this model to evaluate brain-directed therapies. Neonatal mo-br mice received lateral ventricle injections of either adeno-associated virus serotype 5 (AAV5) harboring a reduced-size human ATP7A (rsATP7A) complementary DNA (cDNA), copper chloride, or both. AAV5-rsATP7A showed selective transduction of choroid plexus epithelia and AAV5-rsATP7A plus copper combination treatment rescued mo-br mice; 86% survived to weaning (21 days), median survival increased to 43 days, 37% lived beyond 100 days, and 22% survived to the study end point (300 days). This synergistic treatment effect correlated with increased brain copper levels, enhanced activity of dopamine-β-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. Our findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease.
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Minghetti M, Leaver MJ, Taggart JB, Casadei E, Auslander M, Tom M, George SG. Copper induces Cu-ATPase ATP7A mRNA in a fish cell line, SAF1. Comp Biochem Physiol C Toxicol Pharmacol 2011; 154:93-9. [PMID: 21473932 DOI: 10.1016/j.cbpc.2011.03.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 03/25/2011] [Accepted: 03/28/2011] [Indexed: 01/28/2023]
Abstract
Copper transporting ATPase, ATP7A, is an ATP dependent copper pump present in all vertebrates, critical for the maintenance of intracellular and whole body copper homeostasis. Effects of copper treatment on ATP7A gene expression in fibroblast cells (SAF1) of the sea bream (Sparus aurata) were investigated by qRT-PCR and by a medium density microarray from a closely related species, striped sea bream (Lithognathus mormyrus). To discriminate between the effects of Cu and other metals, SAF1 cells were exposed to sub-toxic levels of Cu, Zn and Cd. Expression of Cu homeostasis genes copper transporter 1 (CTR1), Cu ATPase (ATP7A), Cu chaperone (ATOX1) and metallothionein (MT) together with the oxidative stress markers glutathione reductase (GR) and Cu/Zn superoxide dismutase (CuZn/SOD) were measured 0, 4 and 24 hours post-exposure by qRT-PCR. Microarray was conducted on samples from 4 hours post Cu exposure. Cu, Zn and Cd increased MT and GR mRNA levels, while only Cu increased ATP7A mRNA levels. Microarray results confirmed the effects of Cu on ATP7A and MT and in addition showed changes in the expression of genes involved in protein transport and secretion. Results suggest that ATP7A may be regulated at the transcriptional level directly by Cu and by a mechanism that is different from that exerteted by metals on MT genes.
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Barry AN, Otoikhian A, Bhatt S, Shinde U, Tsivkovskii R, Blackburn NJ, Lutsenko S. The lumenal loop Met672-Pro707 of copper-transporting ATPase ATP7A binds metals and facilitates copper release from the intramembrane sites. J Biol Chem 2011; 286:26585-94. [PMID: 21646353 DOI: 10.1074/jbc.m111.229039] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The copper-transporting ATPase ATP7A has an essential role in human physiology. ATP7A transfers the copper cofactor to metalloenzymes within the secretory pathway; inactivation of ATP7A results in an untreatable neurodegenerative disorder, Menkes disease. Presently, the mechanism of ATP7A-mediated copper release into the secretory pathway is not understood. We demonstrate that the characteristic His/Met-rich segment Met(672)-Pro(707) (HM-loop) that connects the first two transmembrane segments of ATP7A is important for copper release. Mutations within this loop do not prevent the ability of ATP7A to form a phosphorylated intermediate during ATP hydrolysis but inhibit subsequent dephosphorylation, a step associated with copper release. The HM-loop inserted into a scaffold protein forms two structurally distinct binding sites and coordinates copper in a mixed His-Met environment with an ∼2:1 stoichiometry. Binding of either copper or silver, a Cu(I) analog, induces structural changes in the loop. Mutations of 4 Met residues to Ile or two His-His pairs to Ala-Gly decrease affinity for copper. Altogether, the data suggest a two-step process, where copper released from the transport sites binds to the first His(Met)(2) site, triggering a structural change and binding to a second 2-coordinate His-His or His-Met site. We also show that copper binding within the HM-loop stabilizes Cu(I) and protects it from oxidation, which may further aid the transfer of copper from ATP7A to acceptor proteins. The mechanism of copper entry into the secretory pathway is discussed.
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Affiliation(s)
- Amanda N Barry
- From the Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA
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20
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Abstract
This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.
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Chen H, Attieh ZK, Syed BA, Kuo Y, Stevens V, Fuqua BK, Andersen HS, Naylor CE, Evans RW, Gambling L, Danzeisen R, Bacouri‐Haidar M, Usta J, Vulpe CD, McArdle HJ. Identification of zyklopen, a new member of the vertebrate multicopper ferroxidase family, and characterization in rodents and human cells. J Nutr 2010; 140:1728-35. [PMID: 20685892 PMCID: PMC2937573 DOI: 10.3945/jn.109.117531] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
We previously detected a membrane-bound, copper-containing oxidase that may be involved in iron efflux in BeWo cells, a human placental cell line. We have now identified a gene encoding a predicted multicopper ferroxidase (MCF) with a putative C-terminal membrane-spanning sequence and high sequence identity to hephaestin (Heph) and ceruloplasmin (Cp), the other known vertebrate MCF. Molecular modeling revealed conservation of all type I, II, and III copper-binding sites as well as a putative iron-binding site. Protein expression was observed in multiple diverse mouse tissues, including placenta and mammary gland, and the expression pattern was distinct from that of Cp and Heph. The protein possessed ferroxidase activity, and protein levels decreased in cellular copper deficiency. Knockdown with small interfering RNA in BeWo cells indicates that this gene represents the previously detected oxidase. We propose calling this new member of the MCF family "zyklopen."
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Affiliation(s)
- Huijun Chen
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720,Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Zouhair K. Attieh
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720,Department of Laboratory Science and Technology, American University of Science and Technology, Ashrafieh 1100, Lebanon
| | - Basharut A. Syed
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720,Visiongain Ltd, London EC1V 2QY, UK
| | - Yien‐Ming Kuo
- Department of Medicine, University of California, San Francisco, CA 94143
| | - Valerie Stevens
- Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, AB21 9SB, UK
| | - Brie K. Fuqua
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720
| | - Henriette S. Andersen
- Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, AB21 9SB, UK
| | - Claire E. Naylor
- Department of Crystallography, Birkbeck College, London, WC1E 7HX, UK
| | - Robert W. Evans
- Division of Biosciences, Centre for Infection, Immunity and Disease Mechanisms, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex, UB8 3PH, UK
| | - Lorraine Gambling
- Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, AB21 9SB, UK
| | - Ruth Danzeisen
- Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, AB21 9SB, UK,International Copper Association, Inc., New York, NY 10016
| | - Mhenia Bacouri‐Haidar
- Department of Biology, Faculty of Sciences, Lebanese University, Hadath 1500, Lebanon
| | - Julnar Usta
- Department of Biochemistry, School of Medicine, American University of Beirut, Beirut 1103, Lebanon
| | - Chris D. Vulpe
- Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720,To whom correspondence should be addressed. E-mail:
| | - Harry J. McArdle
- Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, AB21 9SB, UK
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22
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Donsante A, Johnson P, Jansen LA, Kaler SG. Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain. Am J Med Genet A 2010; 152A:2529-34. [PMID: 20799318 PMCID: PMC3117432 DOI: 10.1002/ajmg.a.33632] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The primary mechanism of copper transport to the brain is unknown, although this process is drastically impaired in Menkes disease, an X-linked neurodevelopmental disorder caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Potential central nervous system entry routes for copper include brain capillary endothelial cells that originate from mesodermal angioblasts and form the blood-brain barrier, and the choroid plexuses, which derive from embryonic ectoderm, and form the blood-cerebrospinal fluid barrier. We exploited a rare (and first reported) example of somatic mosaicism for an ATP7A mutation to shed light on questions about copper transport into the developing brain. In a 20-month-old Menkes disease patient evaluated before copper treatment, blood copper, and catecholamine concentrations were normal, whereas levels in cerebrospinal fluid were abnormal and consistent with his neurologically severe phenotype. We documented disparate levels of mosaicism for an ATP7A missense mutation, P1001L, in tissues derived from different embryonic origins; allele quantitation showed P1001L in approximately 27% of DNA samples from blood cells (mesoderm-derived) and 88% from cultured fibroblasts (ectoderm-derived). These findings imply that the P1001L mutation in the patient preceded formation of the three primary embryonic lineages at gastrulation, with the ectoderm layer ultimately harboring a higher percentage of mutation-bearing cells than mesoderm or endoderm. Since choroid plexus epithelia are derived from neuroectoderm, and brain capillary endothelial cells from mesodermal angioblasts, the clinical and biochemical findings in this infant support a critical role for the blood-CSF barrier (choroid plexus epithelia) in copper entry to the developing brain.
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Affiliation(s)
- Anthony Donsante
- Unit on Human Copper Metabolism, Molecular Medicine Program, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Paul Johnson
- Unit on Human Copper Metabolism, Molecular Medicine Program, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Laura A. Jansen
- Division of Pediatric Neurology, Seattle Children’s Hospital Research Institute, University of Washington, Seattle, WA
| | - Stephen G. Kaler
- Unit on Human Copper Metabolism, Molecular Medicine Program, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
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23
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Alterations in the expression of the Atp7a gene in the early postnatal development of the mosaic mutant mice (Atp7a mo-ms) - An animal model for Menkes disease. Gene Expr Patterns 2010; 11:41-7. [PMID: 20831904 DOI: 10.1016/j.gep.2010.09.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Revised: 08/30/2010] [Accepted: 09/02/2010] [Indexed: 01/16/2023]
Abstract
Copper is a trace element that is essential for the normal growth and development of all living organisms. In mammals, the ATP7A Cu-transporting ATPase is a key protein that is required for the maintenance of copper homeostasis. In both humans and mice, the ATP7A protein is coded by the X-linked ATP7A/Atp7a gene. Disturbances in copper metabolism caused by mutations in the ATP7A/Atp7a gene lead to severe metabolic syndromes Menkes disease in humans and the lethal mottled phenotype in mice. Mosaic is one of numerous mottled mutations and may serve as a model for a severe Menkes disease variant. In Menkes patients, mutations in the ATP7A gene often result in a decreased level of the normal ATP7A protein. The aim of this study was to analyse the expression of the Atp7a gene in mosaic mutants in early postnatal development, a critical period for starting copper supplementation therapy in both Menkes patients and mutant mice. Using real-time quantitative RT-PCR, we analysed the expression of the Atp7a gene in the brain, kidney and liver of newborn (P0.5) and suckling (P14) mice. Our results indicate that in mosaic P0.5 mutants, the Atp7a mRNA level is decreased in all analysed organs in comparison with wild-type animals. In two week-old mutants, a significant decrease was observed only in the kidney. In contrast, their hepatic level of Atp7a tended to be higher than in wild-type mice. We speculate that disturbance in the expression of the Atp7a gene and, consequently, change in the copper concentration of the organs, may contribute to the early fatal outcome of mosaic males.
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24
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Lenartowicz M, Wieczerzak K, Krzeptowski W, Dobosz P, Grzmil P, Starzyński R, Lipiński P. Developmental changes in the expression of the Atp7a gene in the liver of mice during the postnatal period. ACTA ACUST UNITED AC 2010; 313:209-17. [PMID: 20084666 DOI: 10.1002/jez.586] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
In all living organisms trace element metabolism and transport are closely regulated at the genetic level. Copper is one of the essential microelements required for normal growth and development. The main organ in mammals involved in copper metabolism is the liver. It is known that copper metabolism in the liver is controlled by ATP7B, a P-type ATP-ase encoded by the Atp7b gene. However, little is known about the expression and function of the second important P-type ATP-ase, ATP7A encoded by the Atp7a gene. In this study we investigated the expression of the Atp7a gene in the liver during postnatal development in mice. We analyzed expression of Atp7a gene in the livers from neonatal (P.05), young (P14) and adult (P240) mice using RT-PCR and real-time PCR method. We found a transcript of the Atp7a gene in the liver of all investigated animals. Moreover, we found that the expression of the Atp7a gene in the liver in mice is age-dependent and decreases during postnatal development. Interestingly, the Atp7a expression in adult mice is very low in comparison with neonatal and young animals. Western blot analysis revealed that Atp7a is expressed not only at mRNA level but also at the protein level in the liver of all investigated animals. The expression of Atp7a gene and ATP7A protein was also confirmed in primary hepatocytes from adult mouse. Demonstration of the hepatic Atp7a gene expression may shed light on new aspects of copper metabolism in the liver in mammals.
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Affiliation(s)
- Małgorzata Lenartowicz
- Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland.
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25
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26
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van den Berghe PVE, Klomp LWJ. New developments in the regulation of intestinal copper absorption. Nutr Rev 2010; 67:658-72. [PMID: 19906252 DOI: 10.1111/j.1753-4887.2009.00250.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The transition metal copper is an essential trace element involved in many enzymatic processes that require redox-chemistry. The redox-activity of copper is potentially harmful. Severe imbalance of copper homeostasis can occur with some hereditary disorders of copper metabolism. Copper is acquired from the diet by intestinal absorption and is subsequently distributed throughout the body. The regulation of intestinal copper absorption to maintain whole-body copper homeostasis is currently poorly understood. This review evaluates novel findings regarding the molecular mechanism of intestinal copper uptake. The role of recently identified transporters in enterocyte copper uptake and excretion into the portal circulation is described, and the regulation of dietary copper uptake during physiological and pathophysiological conditions is discussed.
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Affiliation(s)
- Peter V E van den Berghe
- Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
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28
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Lutsenko S, Bhattacharjee A, Hubbard AL. Copper handling machinery of the brain. Metallomics 2010; 2:596-608. [DOI: 10.1039/c0mt00006j] [Citation(s) in RCA: 156] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Ibricevic A, Brody SL, Youngs WJ, Cannon CL. ATP7B detoxifies silver in ciliated airway epithelial cells. Toxicol Appl Pharmacol 2009; 243:315-22. [PMID: 20005242 DOI: 10.1016/j.taap.2009.11.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Revised: 11/20/2009] [Accepted: 11/26/2009] [Indexed: 12/26/2022]
Abstract
Silver is a centuries-old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increased cell death in ATP7B shRNA-treated HepG2 cells. In addition, mTEC from ATP7B(-/-) mice showed enhanced loss of ciliated cells compared to wild type. These studies are the first to demonstrate a cell type-specific expression of the Ag+/Cu+ transporters ATP7A, ATP7B, and CTR1 in airway epithelial cells and a role for ATP7B in detoxification of these metals in the lung.
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Affiliation(s)
- Aida Ibricevic
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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van den Berghe PVE, Stapelbroek JM, Krieger E, de Bie P, van de Graaf SFJ, de Groot REA, van Beurden E, Spijker E, Houwen RHJ, Berger R, Klomp LWJ. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology 2009; 50:1783-95. [PMID: 19937698 DOI: 10.1002/hep.23209] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
UNLABELLED Wilson disease (WD) is an autosomal recessive copper overload disorder of the liver and basal ganglia. WD is caused by mutations in the gene encoding ATP7B, a protein localized to the trans-Golgi network that primarily facilitates hepatic copper excretion. Current treatment comprises reduction of circulating copper by zinc supplementation or copper chelation. Despite treatment, a significant number of patients have neurological deterioration. The aim of this study was to investigate the possibility that defects arising from some WD mutations are ameliorated by drug treatment aimed at improvement of protein folding and restoration of protein function. This necessitated systematic characterization of the molecular consequences of distinct ATP7B missense mutations associated with WD. With the exception of p.S1363F, all mutations tested (p.G85V, p.R778L, p.H1069Q, p.C1104F, p.V1262F, p.G1343V, and p.S1363F) resulted in reduced ATP7B protein expression, whereas messenger RNA abundance was unaffected. Retention of mutant ATP7B in the endoplasmic reticulum, increased protein expression, and normalization of localization after culturing cells at 30 degrees C, and homology modeling suggested that these proteins were misfolded. Four distinct mutations exhibited residual copper export capacity, whereas other mutations resulted in complete disruption of copper export by ATP7B. Treatment with pharmacological chaperones 4-phenylbutyrate (4-PBA) and curcumin, a clinically approved compound, partially restored protein expression of most ATP7B mutants. CONCLUSION These findings might enable novel treatment strategies in WD by directly enhancing the protein expression of mutant ATP7B with residual copper export activity. 1795.).
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Affiliation(s)
- Peter V E van den Berghe
- Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, and the Netherlands Metabolomics Center, Utrecht, The Netherlands
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31
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Craig PM, Galus M, Wood CM, McClelland GB. Dietary iron alters waterborne copper-induced gene expression in soft water acclimated zebrafish (Danio rerio). Am J Physiol Regul Integr Comp Physiol 2008; 296:R362-73. [PMID: 18987288 DOI: 10.1152/ajpregu.90581.2008] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metals like iron (Fe) and copper (Cu) function as integral components in many biological reactions, and, in excess, these essential metals are toxic, and organisms must control metal acquisition and excretion. We examined the effects of chronic waterborne Cu exposure and the interactive effects of elevated dietary Fe on gene expression and tissue metal accumulation in zebrafish. Softwater acclimated zebrafish exposed to 8 microg/l Cu, with and without supplementation of a diet high in Fe (560 vs. 140 mg Fe/kg food) for 21 days demonstrated a significant reduction in liver and gut Cu load relative to waterborne Cu exposure alone. Gene expression levels for divalent metal transport (DMT)-1, copper transporter (CTR)-1, and the basolateral metal transporter ATP7A in the gills and gut increased when compared with controls, but the various combinations of Cu and high-Fe diet revealed altered levels of expression. Further examination of the basolateral Fe transporter, ferroportin, showed responses to waterborne Cu exposure in the gut and a significant increase with Fe treatment alone in the liver. Additionally, we examined metallothionein 1 and 2 (MT1 and MT2), which indicated that MT2 is more responsive to Cu. To explore the relationship between transcription and protein function, we examined both CTR-1 protein levels and gill apical uptake of radiolabeled Cu64, which demonstrated decreased Cu uptake and protein abundance in the elevated Cu treatments. This study shows that high dietary Fe can significantly alter the genetic expression pattern of Cu transporters at the level of the gill, liver, and gastrointestinal tract.
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Affiliation(s)
- Paul M Craig
- Department of Biology, McMaster University, 1280 Main St. West, Hamilton, ON L8S 4K1 Canada.
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32
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Lönnerdal B. Intestinal regulation of copper homeostasis: a developmental perspective. Am J Clin Nutr 2008; 88:846S-50S. [PMID: 18779306 DOI: 10.1093/ajcn/88.3.846s] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Stable-isotope studies in human infants and adults have shown that copper homeostasis occurs, but the contribution of the small intestine to this regulation is still not well understood. Copper first needs to be reduced to the cuprous form, most likely by Steap proteins on the apical membrane. Copper is subsequently absorbed by Ctr1 and then transferred in the enterocyte by the chaperone Atox1 to reach ATP7A for export from the cell. The role of ATP7B, shown to be present in the small intestine, is still poorly understood. In situations of high copper exposure, Ctr1 is endocytosed, metallothionein is induced, and ATP7A moves to a more basolateral localization. However, the ontogeny of regulation of copper homeostasis has received little attention. In rat pups, tissue copper and total-body (67)Cu retention decrease throughout postnatal development, whereas liver (67)Cu retention, serum copper, and ceruloplasmin activity increase. Total (67)Cu absorption decreases and intestinal (67)Cu retention increases with increased copper intake. During early infancy (day 10), copper supplementation increases intestinal copper and metallothionein gene expression, and Ctr1 protein levels increase, whereas Atp7A and Atp7B are unaffected. However, during late infancy (day 20), intestinal copper concentrations are unaffected by supplementation, but Ctr1, ATP7A, and Atp7B protein levels are higher than in controls. Thus, maturation of small intestine copper transport occurs through increased abundance and altered localization of Ctr1, Atp7A, and Atp7B. The mechanisms behind this maturation, including both transcriptional and posttranscriptional regulation, require further studies.
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Affiliation(s)
- Bo Lönnerdal
- Department of Nutrition, University of California, Davis, CA 95616, USA.
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33
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Weiss KH, Wurz J, Gotthardt D, Merle U, Stremmel W, Füllekrug J. Localization of the Wilson disease protein in murine intestine. J Anat 2008; 213:232-40. [PMID: 18673401 DOI: 10.1111/j.1469-7580.2008.00954.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Wilson disease is an inherited disorder of human copper metabolism, characterized by gradual accumulation of copper in tissues, predominantly liver and brain. The gene defect lies in the Wilson disease protein ATP7B, a copper transporting ATPase highly active in hepatocytes. In the liver, ATP7B is essential for excretion of excess copper into the bile and for copper loading of ceruloplasmin in the Golgi apparatus. The extrahepatic role of ATP7B is not yet completely understood. We analysed the intestinal expression of ATP7B in mice using RT-PCR, Western blot and indirect immunofluorescence. We found abundant expression of ATP7B in stomach and small intestine, but not in colon. Using confocal microscopy we demonstrate a Golgi localization of ATP7B in enterocytes. In response to elevated copper, the Wilson disease protein shows an intracellular trafficking pattern in the intestinal polarized cell line CaCo-2, moving away from the Golgi apparatus to dispersed vesicles. This suggests a role for intestinal ATP7B in sequestration of copper in intracellular vesicles for maintenance of copper homeostasis in the enterocyte. In conclusion, the expression of ATP7B in the small intestine might represent an additional regulatory mechanism to fine-tune intestinal copper absorption.
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Affiliation(s)
- Karl Heinz Weiss
- Department of Gastroenterology, University of Heidelberg, Heidelberg, Germany.
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34
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Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance. Arch Biochem Biophys 2008; 476:22-32. [PMID: 18534184 DOI: 10.1016/j.abb.2008.05.005] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2008] [Revised: 05/06/2008] [Accepted: 05/13/2008] [Indexed: 11/23/2022]
Abstract
The human copper-transporting ATPases (Cu-ATPases) are essential for dietary copper uptake, normal development and function of the CNS, and regulation of copper homeostasis in the body. In a cell, Cu-ATPases maintain the intracellular concentration of copper by transporting copper into intracellular exocytic vesicles. In addition, these P-type ATPases mediate delivery of copper to copper-dependent enzymes in the secretory pathway and in specialized cell compartments such as secretory granules or melanosomes. The multiple functions of human Cu-ATPase necessitate complex regulation of these transporters that is mediated through the presence of regulatory domains in their structure, posttranslational modification and intracellular trafficking, as well as interactions with the copper chaperone Atox1 and other regulatory molecules. In this review, we summarize the current information on the function and regulatory mechanisms acting on human Cu-ATPases ATP7A and ATP7B. Brief comparison with the Cu-ATPase orthologs from other species is included.
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35
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Linz R, Lutsenko S. Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. J Bioenerg Biomembr 2008; 39:403-7. [PMID: 18000748 DOI: 10.1007/s10863-007-9101-2] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Copper plays an essential role in human physiology and is indispensable for normal growth and development. Enzymes that are involved in connective tissue formation, neurotransmitter biosynthesis, iron transport, and others essential physiological processes require copper as a cofactor to mediate their reactions. The biosynthetic incorporation of copper into these enzymes takes places within the secretory pathway and is critically dependent on the activity of copper-transporting ATPases ATP7A or ATP7B. In addition, ATP7A and ATP7B regulate intracellular copper concentration by removing excess copper from the cell. These two transporters belong to the family of P(1)-type ATPases, share significant sequence similarity, utilize the same general mechanism for their function, and show partial colocalization in some cells. However, the distinct biochemical characteristics and dissimilar trafficking properties of ATP7A and ATP7B in cells, in which they are co-expressed, indicate that specific functions of these two copper-transporting ATPases are not identical. Immuno-detection studies in cells and tissues have begun to suggest specific roles for ATP7A and ATP7B. These experiments also revealed technical challenges associated with quantitative detection of copper-transporting ATPases in tissues, as illustrated here by comparing the results of ATP7A and ATP7B immunodetection in mouse cerebellum.
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Affiliation(s)
- Rachel Linz
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA
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36
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Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev 2007; 87:1011-46. [PMID: 17615395 DOI: 10.1152/physrev.00004.2006] [Citation(s) in RCA: 596] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B are evolutionarily conserved polytopic membrane proteins with essential roles in human physiology. The Cu-ATPases are expressed in most tissues, and their transport activity is crucial for central nervous system development, liver function, connective tissue formation, and many other physiological processes. The loss of ATP7A or ATP7B function is associated with severe metabolic disorders, Menkes disease, and Wilson disease. In cells, the Cu-ATPases maintain intracellular copper concentration by transporting copper from the cytosol across cellular membranes. They also contribute to protein biosynthesis by delivering copper into the lumen of the secretory pathway where metal ion is incorporated into copper-dependent enzymes. The biosynthetic and homeostatic functions of Cu-ATPases are performed in different cell compartments; targeting to these compartments and the functional activity of Cu-ATPase are both regulated by copper. In recent years, significant progress has been made in understanding the structure, function, and regulation of these essential transporters. These studies raised many new questions related to specific physiological roles of Cu-ATPases in various tissues and complex mechanisms that control the Cu-ATPase function. This review summarizes current data on the structural organization and functional properties of ATP7A and ATP7B as well as their localization and functions in various tissues, and discusses the current models of regulated trafficking of human Cu-ATPases.
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Affiliation(s)
- Svetlana Lutsenko
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
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37
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de Bie P, Muller P, Wijmenga C, Klomp LWJ. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet 2007; 44:673-88. [PMID: 17717039 PMCID: PMC2752173 DOI: 10.1136/jmg.2007.052746] [Citation(s) in RCA: 257] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.
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Affiliation(s)
- P de Bie
- Laboratory of Metabolic and Endocrine Diseases, Room KC.02.069.1, Lundlaan 6, 3584 EA Utrecht, The Netherlands
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38
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La Fontaine S, Mercer JFB. Trafficking of the copper-ATPases, ATP7A and ATP7B: Role in copper homeostasis. Arch Biochem Biophys 2007; 463:149-67. [PMID: 17531189 DOI: 10.1016/j.abb.2007.04.021] [Citation(s) in RCA: 328] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2007] [Revised: 04/18/2007] [Accepted: 04/18/2007] [Indexed: 01/05/2023]
Abstract
Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.
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Affiliation(s)
- Sharon La Fontaine
- Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, 221 Burwood Highway, Burwood, Vic. 3125, Australia.
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39
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Kuo YM, Hayflick SJ, Gitschier J. Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration. J Inherit Metab Dis 2007; 30:310-7. [PMID: 17429753 PMCID: PMC2099457 DOI: 10.1007/s10545-007-0560-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2007] [Revised: 03/02/2007] [Accepted: 03/06/2007] [Indexed: 10/23/2022]
Abstract
We asked whether a movement disorder could be elicited by deprivation of pantothenic acid (PA; vitamin B5), the substrate for the enzyme pantothenate kinase 2 (PANK2), which is deficient in the inherited neurological disorder PKAN (pantothenate kinase-associated neurodegeneration formerly called Hallervorden-Spatz syndrome). This study was undertaken because mice made null for Pank2 failed to show the neurological manifestations of the human disease. Wild-type and Pank2 mutant mice were fed pantothenic acid-deficient diets and were monitored for general health, fertility and movement compared with animals on control diets over time. Mice of both genotypes on PA-deficient diets exhibited poor grooming, greying of fur and decreased body weight. With PA deprivation, wild-type mice manifested azoospermia (a phenotype also seen in Pank2 mice) as well as a movement disorder with a low-lying pelvis and slow steps. Rear limbs appeared to drag and occasionally extended into unnatural postures for 16-17 s duration, possibly indicative of dystonia. Movement disruption probably also occurs in PA-deprived Pank2 mutant mice, but they died precipitously before undergoing detailed analysis. Remarkably, restoration of dietary PA led to recovery of general health and grooming, weight gain, reversal of the movement disorder, and reappearance of mature sperm within 4 weeks. This study confirms the primacy of PA metabolism in the mechanism of disease in PKAN. PA deprivation provides a useful phenocopy for PKAN and allows us to test pharmacological and other interventional strategies in the treatment of this devastating disease.
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Affiliation(s)
- Y. M. Kuo
- Departments of Medicine and Pediatrics, University of California, San Francisco, CA, USA
| | - S. J. Hayflick
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| | - J. Gitschier
- Institute for Human Genetics, UCSF, 513 Parnassus Avenue, HSE 901, San Francisco, CA 94143-0794, USA, e-mail:
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40
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Niciu MJ, Ma XM, El Meskini R, Ronnett GV, Mains RE, Eipper BA. Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Neuroscience 2006; 139:947-64. [PMID: 16549268 DOI: 10.1016/j.neuroscience.2006.01.044] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2005] [Revised: 01/16/2006] [Accepted: 01/26/2006] [Indexed: 11/27/2022]
Abstract
ATP7A is a P-type ATPase that transports copper from cytosol into the secretory pathway for loading onto cuproproteins or efflux. Mutations in Atp7a cause Menkes disease, a copper-deficiency disorder fatal in the postnatal period due to severe neurodegeneration. Early postnatal copper injections are known to diminish degenerative changes in some human patients and mice bearing mutations in Atp7a. In situ hybridization studies previously demonstrated that ATP7A transcripts are expressed widely in the brain. ATP7A-specific antibody was used to study the neurodevelopmental expression and localization of ATP7A protein in the mouse brain. Based on immunoblot analyses, ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum. In the developing and adult brain, ATP7A levels are greatest in the choroid plexus/ependymal cells of the lateral and third ventricles. ATP7A expression decreases in most neuronal subpopulations from birth to adulthood. In contrast, ATP7A expression increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons. ATP7A is expressed in a subset of astrocytes, microglia, oligodendrocytes, tanycytes and endothelial cells. ATP7A is largely localized to the trans-Golgi network, adopting the cell-specific and developmentally-regulated morphology of this organelle. The presence of ATP7A in the axons of postnatal, but not adult, optic nerve suggests stage-specific roles for this enzyme. In sum, the precisely-regulated neurodevelopmental expression of ATP7A correlates well with the limited therapeutic window for effective treatment of Menkes disease.
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Affiliation(s)
- M J Niciu
- University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047, 263 Farmington Avenue, Farmington, CT 06030, USA
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41
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Huster D, Finegold MJ, Morgan CT, Burkhead JL, Nixon R, Vanderwerf SM, Gilliam CT, Lutsenko S. Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:423-34. [PMID: 16436657 PMCID: PMC1606493 DOI: 10.2353/ajpath.2006.050312] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b-/- mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b-/- livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.
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Affiliation(s)
- Dominik Huster
- Department of Biochemistry, Oregon Health & Science University, Portland, Oregon, USA
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Kuo YM, Gybina AA, Pyatskowit JW, Gitschier J, Prohaska JR. Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J Nutr 2006; 136:21-6. [PMID: 16365053 PMCID: PMC2718570 DOI: 10.1093/jn/136.1.21] [Citation(s) in RCA: 159] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Studies were conducted to determine distribution of the copper transporter, Ctr1, a transmembrane protein responsible for cellular copper uptake, in adult mice and in suckling mice nursed by either copper-adequate (Cu+) or copper-deficient (Cu-) dams. Western immunoblot analyses, using immunopurified antibody, detected monomeric (23 kDa) and oligomeric forms of Ctr1 in the membrane fraction of several mouse organs. Immunohistochemical analyses detected abundant Ctr1 protein in liver canaliculi; kidney cortex tubules; small intestinal enterocytes; the choroid plexus and capillaries of brain; intercalated disks of heart; mature spermatozoa; epithelium of mammary ducts; and the pigment epithelium, outer limiting membrane, and outer plexiform layer of the retina. Duodenal Ctr1 distribution was different in the adult compared with suckling mice; adult mice demonstrated strong intracellular staining of the enterocyte, whereas apical staining predominated in suckling mice. In Cu- mice at postnatal d 16 (P16), Ctr1 staining was augmented in kidney, duodenum, and choroid plexus, compared with Cu+ mice. Brain immunoblot data indicated that Ctr1 protein in membrane fractions of Cu- mice was 56% higher than Cu+ mice. Cu- mice had lower hemoglobin (56% of Cu+), and lower copper concentration (% of Cu+) in liver (15%), brain (26%), and kidney (65%). These results suggest that Ctr1 protein is expressed in multiple tissues and found in higher levels in selected organs after perinatal copper deficiency. Enhanced Ctr1 levels and redistribution might compensate in part for the decrease in copper supply. Mechanisms for the enhancement in Ctr1 staining remain to be established.
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Affiliation(s)
- Yien-Ming Kuo
- Departments of Medicine and Pediatrics and the Howard Hughes Medical Institute, University of California, San Francisco, CA
| | - Anna A. Gybina
- Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN
| | - Joshua W. Pyatskowit
- Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN
| | - Jane Gitschier
- Departments of Medicine and Pediatrics and the Howard Hughes Medical Institute, University of California, San Francisco, CA
| | - Joseph R. Prohaska
- Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN
- To whom correspondence should be addressed. E-mail:
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Shi Z, Liang XL, Lu BX, Pan SY, Chen X, Tang QQ, Wang Y, Huang F. Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation. World J Gastroenterol 2005; 11:3691-5. [PMID: 15968722 PMCID: PMC4316018 DOI: 10.3748/wjg.v11.i24.3691] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the therapeutic effect of intrasplenic transplantation with embryonic hepatocytes on amelioration of hereditary copper accumulation in toxic milk (TX) mouse modeling Wilson disease.
METHODS: Donor hepatocytes were harvested from 14-d fetal liver of a pregnant homogeneous DL mouse. These cells were successively cultured, labeled with fluorescein dye Hoechst 33342 for 24 h, and sequentially infused into the spleen parenchyma of the recipient TX mice. No host immunosuppression measures were taken. Two and four weeks after transplantation, the recipients were killed for routine histologic investigation and immunohistochemistry study up to 4 wk after transplantation. The serum copper and ceruloplasmin concentrations of the recipient mice were determined by graphite furnace atomic absorption spectroscopy.
RESULTS: In the following 2nd and 4th wk after transplantation, the donor hepatocytes could be visualized in the livers of 47.3% recipients. The serum ceruloplasmin and copper concentrations increased by 1.6-fold after 2 wk and 2.0-fold times after 4 wk respectively, which ultimately rose from about 30% of the normal level to nearly 60% (P<0.01). The hepatic copper concentration decreased 7.2%, 4 wk after transplantation. Pathologic examination showed that there were many actively proliferative hepatocyte precursor cells with specific embryonic hepatocyte marker AFP migrated into hepatic sinusoids of the recipients. A large number of cells carrying hepatocytes marker and albumin were observed in the recipient spleen tissues.
CONCLUSION: Embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo. After transplantation, the hereditary abnormalities of copper metabolism in TX mice could be corrected partially by intrasplenic transplantation of homogeneous embryonic hepatocytes.
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Affiliation(s)
- Zhu Shi
- Department of Neurology, Nanfang Hospital, 1st Military Medical University, Guangzhou 510515, Guangdong Province, China.
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Bauerly KA, Kelleher SL, Lönnerdal B. Effects of copper supplementation on copper absorption, tissue distribution, and copper transporter expression in an infant rat model. Am J Physiol Gastrointest Liver Physiol 2005; 288:G1007-14. [PMID: 15591161 DOI: 10.1152/ajpgi.00210.2004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Infants are exposed to variable copper (Cu) intake; Cu in breast milk is low, whereas infant formulas vary in Cu content as well as the water used for their preparation. Little is known about the regulation of Cu absorption during infancy. The objectives of this study were to determine effects of Cu supplementation on Cu absorption and tissue distribution and the expression of Cu transporters in an infant rat model. Suckling rat pups were orally dosed with 0, 10, or 25 microg Cu/day. Intestine and liver were collected at days 10 and 20, and Cu concentration, Cu transporter-1 (Ctr1), Atp7A, Atp7B, and metallothionein (MT) mRNA and protein levels were measured. 67Cu absorption was measured at days 10 and 20. Total 67Cu absorption decreased, and intestinal 67Cu retention increased with increased Cu intake. At day 10, intestine Cu concentration, MT mRNA, and Ctr1 protein levels increased with supplementation, but no changes in Atp7A or Atp7B levels were observed. At day 20, intestine Cu concentration was unaffected by Cu supplementation, but Ctr1 protein and Atp7A mRNA and protein levels were higher than in controls. In liver, Cu level reflected Cu intake at days 10 and 20. There was a significant increase in Ctr1, Atp7B, and MT mRNA expression in liver at both ages with Cu supplementation. In conclusion, the ability of suckling rat pups to tolerate varying amounts of dietary Cu may be due to changes in Cu transporters, facilitated by transcriptional and posttranslational mechanisms. Despite these adaptive changes, Cu supplementation resulted in elevated alanine aminotransferase levels, suggesting a risk of Cu toxicity with supplementation during infancy.
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Affiliation(s)
- Kathryn A Bauerly
- Department of Nutrition, University of California Davis, One Shields Ave., Davis, California 95616, USA
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Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem 2005; 280:9640-5. [PMID: 15634671 DOI: 10.1074/jbc.m413840200] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Copper is essential for brain metabolism, serving as a cofactor to superoxide dismutase, dopamine-beta-hydroxylase, amyloid precursor protein, ceruloplasmin, and other proteins required for normal brain function. The copper-transporting ATPases ATP7A and ATP7B play a central role in distribution of copper in the central nervous system; genetic mutations in ATP7A and ATP7B lead to severe neurodegenerative disorders, Menkes disease and Wilson disease, respectively. Although both ATP7A and ATP7B are required, their specific roles and regulation in the brain remain poorly understood. Using high-resolution imaging and functional assays, we demonstrate that ATP7A and ATP7B show cell-specific distribution in adult cerebellum, have distinct enzymatic characteristics, and are regulated differently during development. ATP7B is continuously expressed in Purkinje neurons (PN) where it delivers copper to the ferroxidase ceruloplasmin. ATP7A is a faster copper transporter than Wilson disease protein as evidenced by faster rates of catalytic reactions. The expression of ATP7A switches during development from PN to Bergmann glia, the cells supporting PN function in adult brain. Inactivation of ATP7B (Wilson disease protein) by gene knock-out induces a striking shift in the expression of the ATP7B target protein, ceruloplasmin, from PN to Bergmann glia, where ATP7A (Menkes disease protein) is present. The induced cell-specific change in expression restores copper delivery to ceruloplasmin via ATP7A. Overall, the results provide evidence for distinct functions of ATP7A and ATP7B in the cerebellum and illustrate a tight link between copper homeostasis in PN and Bergmann glia.
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Affiliation(s)
- Natalie Barnes
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239-3098, USA
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Taibjee SM, Bennett DC, Moss C. Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes. Br J Dermatol 2004; 151:269-82. [PMID: 15327534 DOI: 10.1111/j.1365-2133.2004.06057.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
There is increasing evidence that hypomelanosis of Ito and related disorders such as linear and whorled naevoid hypermelanosis are due to mosaicism for a variety of chromosomal abnormalities. This group of disorders is better termed 'pigmentary mosaicism'. In this review we explain how disparate chromosomal abnormalities might manifest as a common pigmentary phenotype. In particular, we provide evidence supporting the hypothesis that the chromosomal abnormalities reported in these disorders specifically disrupt expression or function of pigmentary genes.
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Affiliation(s)
- S M Taibjee
- Department of Dermatology, Birmingham Children's Hospital, Birmingham, UK.
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Kuo YM, Duncan JL, Westaway SK, Yang H, Nune G, Xu EY, Hayflick SJ, Gitschier J. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum Mol Genet 2004; 14:49-57. [PMID: 15525657 PMCID: PMC2117329 DOI: 10.1093/hmg/ddi005] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.
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Affiliation(s)
- Yien-Ming Kuo
- Department of Medicine, University of California, San Francisco, CA, USA
- Department of Pediatrics, University of California, San Francisco, CA, USA
- Howard Hughes Medical Institute, University of California, San Francisco, CA, USA
| | - Jacque L. Duncan
- Department of Ophthalmology, University of California, San Francisco, CA, USA
| | - Shawn K. Westaway
- Department of Molecular and Medical Genetics, Oregon Health and Science University, OR, USA
| | - Haidong Yang
- Department of Ophthalmology, University of California, San Francisco, CA, USA
| | - George Nune
- Department of Ophthalmology, University of California, San Francisco, CA, USA
| | - Eugene Yujun Xu
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA
| | - Susan J. Hayflick
- Department of Molecular and Medical Genetics, Oregon Health and Science University, OR, USA
| | - Jane Gitschier
- Department of Medicine, University of California, San Francisco, CA, USA
- Department of Pediatrics, University of California, San Francisco, CA, USA
- Howard Hughes Medical Institute, University of California, San Francisco, CA, USA
- *To whom correspondence should be addressed at: HSE-901, PO Box 0794, University of California, San Francisco, CA 94143, USA. Tel: +1 4154768729; Fax: +1 4155020720;
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Abstract
Copper is a trace element, important for the function of many cellular enzymes. Copper ions can adopt distinct redox states oxidized Cu(II) or reduced (I), allowing the metal to play a pivotal role in cell physiology as a catalytic cofactor in the redox chemistry of enzymes, mitochondrial respiration, iron absorption, free radical scavenging and elastin cross-linking. If present in excess, free copper ions can cause damage to cellular components and a delicate balance between the uptake and efflux of copper ions determines the amount of cellular copper. In biological systems, copper homeostasis has been characterized at the molecular level. It is coordinated by several proteins such as glutathione, metallothionein, Cu-transporting P-type ATPases, Menkes and Wilson proteins and by cytoplasmic transport proteins called copper chaperones to ensure that it is delivered to specific subcellular compartments and thereby to copper-requiring proteins.
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Affiliation(s)
- H Tapiero
- Université de Paris - Faculté de Pharmacie CNRS UMR 8612, 5, rue Jean-Baptiste-Clément, 94200, Chatenay-Malabry, France.
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Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 2002; 71:66-73. [PMID: 12032886 PMCID: PMC419995 DOI: 10.1086/341125] [Citation(s) in RCA: 320] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2002] [Accepted: 04/08/2002] [Indexed: 11/03/2022] Open
Abstract
The rare inherited condition acrodermatitis enteropathica (AE) results from a defect in the absorption of dietary zinc. Recently, we used homozygosity mapping in consanguineous Middle Eastern kindreds to localize the AE gene to an approximately 3.5-cM region on 8q24. In this article, we identify a gene, SLC39A4, located in the candidate region and, in patients with AE, document mutations that likely lead to the disease. The gene encodes a histidine-rich protein, which we refer to as "hZIP4," which is a member of a large family of transmembrane proteins, some of which are known to serve as zinc-uptake proteins. We show that Slc39A4 is abundantly expressed in mouse enterocytes and that the protein resides in the apical membrane of these cells. These findings suggest that the hZIP4 transporter is responsible for intestinal absorption of zinc.
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Affiliation(s)
- Kun Wang
- Howard Hughes Medical Institute and Department of Medicine, University of California, San Francisco, 94143, USA
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Zhou B, Bae SK, Malone AC, Levinson BB, Kuo YM, Cilio MR, Bertini E, Hayflick SJ, Gitschier JM. hGFRalpha-4: a new member of the GDNF receptor family and a candidate for NBIA. Pediatr Neurol 2001; 25:156-61. [PMID: 11551746 DOI: 10.1016/s0887-8994(00)00277-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Hallervorden-Spatz syndrome (neurodegeneration with brain iron accumulation type 1; OMIM entry 234200) is a rare inherited neurodegenerative disease. In this article, evidence for a newly identified gene as a candidate for Hallervorden-Spatz syndrome is given. Previously Hallervorden-Spatz syndrome was mapped to a 4-cm region in 20p12.3-13. During positional cloning efforts a new member of the glial-derived neurotrophic factor receptor family was discovered in this region. Like other members of this receptor family, this new gene is predicted to be secreted and glycosyl-phosphatidylinositol linked, and it maintains conserved cysteine residues. However, cDNA and genomic studies in both humans and mice indicate that this gene lacks the sequence corresponding to exons 2 and 3 in other family members. In situ hybridization reveals that it is expressed primarily in the brain and bladder in the embryonic mouse. Mutation analysis of patients with Hallervorden-Spatz syndrome revealed two potentially significant amino acid changes in two patients but failed to identify mutations in the remaining 10 subjects. The implication of these findings for the relationship between this gene and Hallervorden-Spatz syndrome is discussed.
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Affiliation(s)
- B Zhou
- Howard Hughes Medical Institute and Department of Medicine and Pediatrics, University of California, San Francisco, California 94143, USA
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