Impairment of interrelated ironand copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders

Frontiers in Pharmacology

Volumn 3 SEP, Issue , 2012, Pages

  Skjørringe, Tina ^a,b   Møller, Lisbeth Birk ^b   Moos, Torben ^a  

^a AALBORG UNIVERSITY   (Denmark)

^b Rigshospitalet   (Denmark)

Author keywords

Blood brain barrier; Cerebrospinal fluid; Copper; Homeostasis; Iron; Neurodegenerative disorders

Indexed keywords

COPPER; FERROPORTIN; IRON; MESSENGER RNA; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; TRANSFERRIN RECEPTOR;

ALZHEIMER DISEASE; ARTICLE; BLOOD BRAIN BARRIER; BLOOD CEREBROSPINAL FLUID BARRIER; BRAIN CIRCULATION; BRAIN DEGENERATION; BRAIN METABOLISM; BRAIN NERVE CELL; COPPER DEFICIENCY; COPPER METABOLISM; DEGENERATIVE DISEASE; DIETARY INTAKE; DISEASE ASSOCIATION; FERROPORTIN GENE; GENE EXPRESSION REGULATION; GENE MUTATION; GLIA CELL; HUMAN; HUNTINGTON CHOREA; IRON DEFICIENCY; IRON METABOLISM; IRON TRANSPORT; METABOLIC REGULATION; MOLECULAR INTERACTION; MOLECULAR PATHOLOGY; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2 GENE; NEUROPATHOLOGY; NONHUMAN; PARKINSON DISEASE; PROTEIN EXPRESSION; TRANS GOLGI NETWORK; TRANSFERRIN RECEPTOR GENE;

EID: 84867132546     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2012.00169     Document Type: Article

References (171)

1. Abbott, N. J., Ronnback, L., and Hansson,E. (2006).Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41-53.
2. Anderson, G. J., Frazer, D. M., McKie, A. T., and Vulpe, C. D. (2002). The ceruloplasmin homolog hephaestin and the control of intestinal iron absorption. Blood Cells Mol. Dis. 29, 367-375.
3. Arnal, N., Cristalli, D. O., de Alaniz, M. J., and Marra, C. A. (2010). Clinical utility of copper, ceruloplasmin, and metallothionein plasma determinations in human neurodegenerative patients and their firstdegree relatives. Brain Res. 1319, 118-130.
4. Arredondo, M., Munoz, P., Mura, C. V., and Nunez, M. T. (2003). DMT1, a physiologically relevant apical Cu1+ transporter of intestinal cells. Am. J. Physiol. Cell Physiol. 284, C1525-C1530.
5. Barnes, N., Tsivkovskii, R., Tsivkovskaia, N., and Lutsenko, S. (2005). The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. J. Biol. Chem. 280, 9640-9645.
6. Bartzokis, G., Tishler, T. A., Shin, I. S., Lu, P. H., and Cummings, J. L. (2004). Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann. N. Y. Acad. Sci. 1012, 224-236.
7. Basha, M. R., Wei, W., Bakheet, S. A., Benitez, N., Siddiqi, H. K., Ge, Y. W., Lahiri, D. K., and Zawia, N. H.(2005). The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J. Neurosci. 25, 823-829.
8. Bastian, T. W., Prohaska, J. R., Georgieff, M. K., and Anderson, G. W. (2010). Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology 151, 4055-4065.
9. Beard, J. L., and Connor, J. R. (2003). Iron status and neural functioning. Annu. Rev. Nutr. 23, 41-58.
10. Beard, J. L., Felt, B., Schallert, T., Burhans, M., Connor, J. R., and Georgieff, M. K. (2006). Moderate iron deficiency in infancy: biology and behavior in young rats. Behav. Brain Res. 170, 224-232.
11. Begley, D. J., and Brightman, M. W. (2003). Structural and functional aspects of the blood-brain barrier. Prog. Drug Res. 61, 39-78.
12. Benkovic, S. A., and Connor, J. R. (1993). Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. J. Comp. Neurol. 338, 97-113.
13. Brewer, G. J., Askari, F., Lorincz, M. T., Carlson, M., Schilsky, M., Kluin, K. J., Hedera, P., Moretti, P., Fink, J. K., Tankanow, R., Dick, R. B., and Sitterly, J. (2006). Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch. Neurol. 63, 521-527.
14. Brewer, G. J., Hedera, P., Kluin, K. J., Carlson, M., Askari, F., Dick, R. B., Sitterly, J., and Fink, J. K. (2003). Treatment of Wilson disease with ammonium tetrathiomolybdate: III Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch. Neurol. 60, 379-385.
15. Brewer, G. J., Kanzer, S. H., Zimmerman, E. A., Celmins, D. F., Heckman, S. M., and Dick, R. (2010). Copper and ceruloplasmin abnormalities in Alzheimer's disease. Am. J. Alzheimers Dis. Other Demen. 25, 490-497.
16. Bucossi, S., Mariani, S., Ventriglia, M., Polimanti, R., Gennarelli, M., Bonvicini, C., Pasqualetti, P., Scrascia, F., Migliore, S., Vernieri, F., Rossini, P. M., and Squitti, R. (2011a). Association between the c. 2495 A>G ATP7B polymorphism and sporadic Alzheimer's disease. Int. J. Alzheimers Dis. 2011, 973692.
17. Bucossi, S., Ventriglia, M., Panetta, V., Salustri, C., Pasqualetti, P., Mariani, S., Siotto, M., Rossini, P. M., and Squitti, R. (2011b). Copper in Alzheimer's disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J. Alzheimers Dis. 24, 175-185.
18. Bucossi, S., Polimanti, R., Mariani, S., Ventriglia, M., Bonvicini, C., Migliore, S., Manfellotto, D., Salustri, C., Vernieri, F., Rossini, P. M., and Squitti, R. (2012). Association of K832R and R952K SNPs of Wilson's Disease Gene with Alzheimer's Disease. J. Alzheimers Dis. 29, 913-919.
19. Burdo, J. R., Menzies, S. L., Simpson, I. A., Garrick, L. M., Garrick, M. D., Dolan, K. G., Haile, D. J., Beard, J. L., and Connor, J. R. (2001). Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J. Neurosci. Res. 66, 1198-1207.
20. Carlson, E. S., Magid, R., Petryk, A., and Georgieff, M. K. (2008). Iron deficiency alters expression of genes implicated in Alzheimer disease pathogenesis. Brain Res. 1237, 75-83.
21. Carlson, E. S., Tkac, I., Magid, R., O'Connor, M. B., Andrews, N. C., Schallert, T., Gunshin, H., Georgieff, M. K., and Petryk, A. (2009). Iron is essential for neuron development and memory function in mouse hippocampus. J. Nutr. 139, 672-679.
22. Caselli, R. J., Beach, T. G., Yaari, R., and Reiman, E. M. (2006). Alzheimer's disease a century later. J. Clin. Psy-chiatry 67, 1784-1800.
23. Cheah, J. H., Kim, S. F., Hester, L. D., Clancy, K. W., Patterson, S. E. III, Papadopoulos, V., and Snyder, S. H. (2006). NMDA receptornitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron 51, 431-440.
24. Chen, H., Attieh, Z. K., Syed, B. A., Kuo, Y. M., Stevens, V., Fuqua, B. K., Andersen, H. S., Naylor, C. E., Evans, R. W., Gambling, L., Danzeisen, R., Bacouri-Haidar, M., Usta, J., Vulpe, C. D., and McArdle, H. J. (2010). Identification of zyklopen, a new member of the vertebrate multicopper ferroxidase family, and characterization in rodents and human cells. J. Nutr. 140, 1728-1735.
25. Choi, B. S., and Zheng, W. (2009). Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res. 1248, 14-21.
26. Choudhuri, S., Cherrington, N. J., Li, N., and Klaassen, C. D. (2003). Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab. Dispos. 31, 1337-1345.
27. Christodoulou, J., Danks, D. M., Sarkar, B., Baerlocher, K. E., Casey, R., Horn, N., Tumer, Z., and Clarke, J. T. (1998). Early treatment of Menkes disease with parenteral copperhistidine: long-term follow-up of four treated patients. Am. J. Med. Genet. 76, 154-164.
28. Collins, J. F., Franck, C. A., Kowdley, K. V., and Ghishan, F. K. (2005). Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G964-G971.
29. Connor, J. R., Boeshore, K. L., Benkovic, S. A., and Menzies, S. L. (1994). Isoforms of ferritin have a specific cellular distribution in the brain. J. Neurosci. Res. 37, 461-465.
30. Connor, J. R., Snyder, B. S., Arosio, P., Loeffler, D. A., and LeWitt, P. (1995). A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J. Neurochem. 65, 717-724.
31. Crowe, A., and Morgan, E. H. (1996). The effects of iron loading and iron deficiency on the tissue uptake of 64Cu during development in the rat. Biochim. Biophys. Acta 1291, 53-59.
32. Curtis, A. R., Fey, C., Morris, C. M., Bindoff, L. A., Ince, P. G., Chinnery, P. F., Coulthard, A., Jackson, M. J., Jackson, A. P., McHale, D. P., Hay, D., Barker, W. A., Markham, A. F., Bates, D., Curtis, A., and Burn, J. (2001). Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet. 28, 350-354.
33. Danzeisen, R., Fosset, C., Chariana, Z., Page, K., David, S., and McArdle, H. J. (2002). Placental ceruloplasmin homolog is regulated by iron and copper and is implicated in iron metabolism. Am. J. Physiol. Cell Physiol. 282, C472-C478.
34. DeBoer, T., Wewerka, S., Bauer, P. J., Georgieff, M. K., and Nelson, C. A. (2005). Explicit memory performance in infants of diabetic mothers at 1 year of age. Dev. Med. Child Neurol. 47, 525-531.
35. Dexter, D. T., Carayon, A., Javoy-Agid, F., Agid, Y., Wells, F. R., Daniel, S. E., Lees, A. J., Jenner, P., and Marsden, C. D. (1991). Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4), 1953-1975.
36. Dexter, D. T., Wells, F. R., Lees, A. J., Agid, F., Agid, Y., Jenner, P., and Marsden, C. D. (1989). Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J. Neurochem. 52, 1830-1836.
37. Duce, J. A., Tsatsanis, A., Cater, M. A., James, S. A., Robb, E., Wikhe, K., Leong, S. L., Perez, K., Johanssen, T., Greenough, M. A., Cho, H. H., Galatis, D., Moir, R. D., Masters, C. L., McLean, C., Tanzi, R. E., Cappai, R., Barnham, K. J., Ciccotosto, G. D., Rogers, J. T., and Bush, A. I. (2010). Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857-867.
38. Dusek,P.,Jankovic,J.,and Le,W. (2012). Iron dysregulation in movement disorders. Neurobiol. Dis. 46, 1-18.
39. Espinoza, A., Le, B. S., Olivares, M., Pizarro, F., Ruz, M., and Arredondo, M. (2012). Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA. Biol. Trace Elem. Res. 146, 281-286.
40. Faucheux, B. A., Martin, M. E., Beaumont, C., Hunot, S., Hauw, J. J., Agid, Y., and Hirsch, E. C. (2002). Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease. J. Neurochem. 83, 320-330.
41. Felt, B. T., Beard, J. L., Schallert, T., Shao, J., Aldridge, J. W., Connor, J. R., Georgieff, M. K., and Lozoff B. (2006). Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav. Brain Res. 171, 261-270.
42. Felt, B. T., and Lozoff, B. (1996). Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J. Nutr. 126, 693-701.
43. Ferenci, P. (2004). Pathophysiology and clinical features of Wilson disease. Metab. Brain Dis. 19, 229-239.
44. Frazer, D. M.,Vulpe, C. D., McKie, A. T., Wilkins, S. J., Trinder, D., Cleghorn, G. J., and Anderson, G. J. (2001). Cloning and gastrointestinal expression of rat hephaestin: relationship to other iron transport proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G931-G939.
45. Gaggelli, E., Kozlowski, H., Valensin, D., and Valensin, G. (2006). Copper homeostasis and neurodegenerative disorders (Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis). Chem. Rev. 106, 1995-2044.
46. Galazka-Friedman, J., Bauminger, E. R., Friedman, A., Barcikowska, M., Hechel, D., and Nowik, I. (1996). Iron in parkinsonian and control substantia nigra -a Mossbauer spectroscopy study. Mov. Disord. 11, 8-16.
47. Gallagher, C. H., Judah, J. D., and Rees, K. R. (1956). The biochemistry of copper deficiency. I Enzymological disturbances, blood chemistry and excretion of amino-acids. Proc. R. Soc. Lond. B Biol. Sci. 144, 134-150.
48. Garrick, M. D., Dolan, K. G., Horbinski, C., Ghio,A. J., Higgins, D., Porubcin, M., Moore, E. G., Hainsworth, L. N., Umbreit, J. N., Conrad, M. E., Feng, L., Lis, A., Roth, J. A., Singleton, S., and Garrick,L. M. (2003a). DMT1: a mammalian transporter for multiple metals. Biometals 16, 41-54.
49. Garrick, M. D., Nunez, M. T., Olivares, M., and Harris, E. D. (2003b). Parallels and contrasts between iron and copper metabolism. Biometals 16, 1-8.
50. Gerhardsson, L., Lundh, T., Minthon, L., and Londos, E. (2008). Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer's disease. Dement. Geri-atr. Cogn. Disord. 25, 508-515.
51. Girijashanker, K., He, L., Soleimani, M., Reed, J. M., Li, H., Liu, Z., Wang, B., Dalton, T. P., and Nebert, D. W. (2008). Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol.Pharmacol. 73, 1413-1423
52. Gitlin, J. D. (2003). Wilson disease. Gastroenterology 125, 1868-1877.
53. Gollan, J. L., and Gollan, T. J. (1998). Wilson disease in 1998:genetic,diagnostic and therapeutic aspects. J. Hepatol. 28(Suppl. 1), 28-36.
54. Grantham-McGregor, S., and Ani, C. (2001). A review of studies on the effect of iron deficiency on cognitive development in children. J. Nutr. 131, 649S-666S.
55. Gregory, A., Westaway, S. K., Holm, I. E., Kotzbauer, P. T., Hogarth, P., Sonek, S., Coryell, J. C., Nguyen, T. M., Nardocci, N., Zorzi, G., Rodriguez, D., Desguerre, I., Bertini, E., Simonati, A., Levinson, B., Dias, C., Barbot, C., Carrilho, I., Santos, M., Malik, I., Gitschier, J., and Hayflick,S. J. (2008). Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71, 1402-1409.
56. Griffiths, P. D., and Crossman, A. R. (1993). Distribution of iron in the basal ganglia and neocortex in postmortem tissue in Parkinson's disease andAlzheimer's disease. Dementia 4, 61-65.
57. Gunshin, H., Mackenzie, B., Berger, U. V., Gunshin, Y., Romero, M. F., Boron, W. F., Nussberger, S., Gollan, J. L., and Hediger, M. A. (1997). Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482-488.
58. Halliwell, B. (1992). Oxygen radicals as key mediators in neurological disease: fact or fiction? Ann. Neurol. 32(Suppl.), S10-S15.
59. Hansen, T. M., Nielsen, H., Bernth, N., and Moos, T. (1999). Expression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain. Brain Res. Mol. Brain Res. 65, 186-197.
60. Huffman, D. L., and O'Halloran, T. V. (2001). Function, structure, and mechanism of intracellular copper trafficking proteins. Annu. Rev. Biochem. 70, 677-701.
61. Hung, I. H., Suzuki, M., Yamaguchi, Y., Yuan, D. S., Klausner, R. D., and Gitlin, J. D. (1997). Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccha-romyces cerevisiae. J. Biol. Chem. 272, 21461-21466.
62. Illing, A. C., Shawki, A., Cunningham, C. L.,and Mackenzie,B. (2012). Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J. Biol. Chem. 287, 30485-30496.
63. Jenkitkasemwong, S., Wang, C. Y., Mackenzie, B., and Knutson, M. D. (2012). Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25, 643-655.
64. Jeong, S. Y., and David, S. (2003). Glycosylphosphatidylinositol anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J. Biol. Chem. 278, 27144-27148.
65. Jiang, L., Ranganathan, P., Lu, Y., Kim, C., and Collins, J. F. (2011). Exploration of the copper-related compensatory response in the Belgrade rat model of genetic iron deficiency. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G877-G886.
66. Jorgenson,L.A.,Sun,M.,O'Connor,M., and Georgieff, M. K. (2005). Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus. Hippocampus 15, 1094-1102.
67. Jorgenson, L. A., Wobken, J. D., and Georgieff, M. K. (2003). Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev. Neurosci. 25, 412-420.
68. Kaler, S. G. (1998). Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr. Dev. Pathol. 1, 85-98.
69. Kaler, S. G., Buist, N. R., Holmes, C. S., Goldstein, D. S., Miller, R. C., and Gahl, W. A. (1995). Early copper therapy in classic Menkes disease patients with a novel splicing mutation. Ann. Neurol. 38, 921-928.
70. Kaur, D., Rajagopalan, S., Chinta, S., Kumar, J., Di, M. D., Cherny, R. A., and Andersen, J. K. (2007). Chronic ferritin expression within murine dopaminergic midbrain neurons results in a progressive age-related neurodegeneration. Brain Res. 1140, 188-194.
71. Keep, R. F., and Jones, H. C. (1990). A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Brain Res. Dev. Brain Res. 56, 47-53.
72. Kelley, B. J., and Petersen, R. C. (2007). Alzheimer's disease and mild cognitive impairment. Neurol. Clin. 25, 577-609.
73. Keogh, M. J., Jonas, P., Coulthard, A., Chinnery, P. F., and Burn, J. (2012). Neuroferritinopathy: a new inborn error of iron metabolism. Neuroge-netics 13, 93-96.
74. Klomp, L. W.,Farhangrazi, Z. S., Dugan, L. L., and Gitlin, J. D. (1996). Ceruloplasmin gene expression in the murine central nervous system. J. Clin. Invest. 98, 207-215.
75. Klomp, L. W., and Gitlin, J. D. (1996). Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum. Mol. Genet. 5, 1989-1996.
76. Kodama, H., Murata, Y., and Kobayashi, M. (1999). Clinical manifestations and treatment of Menkes disease and its variants. Pediatr. Int. 41, 423-429.
77. Koziorowski, D., Friedman, A., Arosio, P., Santambrogio, P., and Dziewulska, D. (2007). ELISA reveals a difference in the structure of substantia nigra ferritin in Parkinson's disease and incidental Lewy body compared to control. Parkinsonism Relat. Disord. 13, 214-218.
78. Kumar, N., Gross, J. B. Jr., and Ahlskog, J. E. (2004). Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 63, 33-39.
79. Kuo, Y. M., Gybina, A. A., Pyatskowit, J. W., Gitschier, J., and Prohaska, J. R. (2006). Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J. Nutr. 136, 21-26.
80. Kwik-Uribe, C. L., Gietzen, D., German, J. B., Golub, M. S., and Keen, C. L. (2000a). Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J. Nutr. 130, 2821-2830.
81. Kwik-Uribe, C. L., Golub, M. S., and Keen, C. L. (2000b). Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation. J. Nutr. 130, 2040-2048.
82. Lane, D. J., Robinson, S. R., Czerwinska, H., Bishop, G. M., and Lawen, A. (2010). Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron. Biochem. J. 432, 123-132.
83. Latunde-Dada, G. O., Takeuchi, K., Simpson, R. J., and McKie, A. T. (2006). Haem carrier protein 1 (HCP1): expression and functional studies in cultured cells. FEBS Lett. 580, 6865-6870.
84. Lech,T.,and Sadlik,J. K. (2007). Copper concentration in body tissues and fluids in normal subjects of southern Poland. Biol. Trace Elem. Res. 118, 10-15.
85. Lee, J., Pena, M. M., Nose, Y., and Thiele, D. J. (2002). Biochemical characterization of the human copper transporter Ctr1. J. Biol. Chem. 277, 4380-4387.
86. Lee, J., Prohaska, J. R., and Thiele, D. J. (2001). Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc. Natl. Acad. Sci. U.S.A. 98, 6842-6847.
87. Levi, S., Cozzi, A., and Arosio, P. (2005). Neuroferritinopathy: a neurodegenerative disorder associated with Lferritin mutation. Best Pract. Res. Clin. Haematol. 18, 265-276.
88. Levy, J. E., Jin, O., Fujiwara, Y., Kuo, F., and Andrews, N. C. (1999). Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396-399.
89. Loeffler, D. A., LeWitt, P. A., Juneau, P. L., Sima, A. A., Nguyen, H. U., DeMaggio, A. J., Brickman, C. M., Brewer, G. J., Dick, R. D., Troyer, M. D., and Kanaley, L. (1996). Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res. 738, 265-274.
90. Logan, J. I., Harveyson, K. B., Wisdom, G. B., Hughes, A. E., and Archbold, G. P. (1994). Hereditary ceruloplasmin deficiency, dementia and diabetes mellitus. QJM 87, 663-670.
91. Lozoff, B., Beard, J., Connor, J., Barbara, F., Georgieff, M., and Schallert, T. (2006). Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr. Rev. 64, S34-S43.
92. Lutsenko, S., Bhattacharjee, A., and Hubbard, A. L. (2010). Copper handling machinery of the brain. Metal-lomics 2, 596-608.
93. Madsen, E., and Gitlin, J. D. (2007). Copper and iron disorders of the brain. Annu. Rev. Neurosci. 30, 317-337.
94. Maktabi, M. A., Heistad, D. D., and Faraci, F. M. (1990). Effects of angiotensin II on blood flow to choroid plexus. Am. J. Physiol. 258, H414-H418.
95. Malik, I., Turk, J., Mancuso, D. J., Montier, L., Wohltmann, M., Wozniak, D. F., Schmidt, R. E., Gross, R. W., and Kotzbauer, P. T. (2008). Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am. J. Pathol. 172, 406-416.
96. Maynard, C. J., Cappai, R., Volitakis, I., Cherny, R. A., White, A. R., Beyreuther, K., Masters, C. L., Bush, A. I., and Li, Q. X. (2002). Overexpression of Alzheimer's disease amyloid-beta opposes the agedependent elevations of brain copper and iron. J. Biol. Chem. 277, 44670-44676.
97. McCarthy, R. C., and Kosman, D. J. (2012). Mechanistic analysis of iron accumulation by endothelial cells of the BBB. Biometals 25, 665-675.
98. McKie, A. T., Barrow, D., LatundeDada, G. O., Rolfs, A., Sager, G., Mudaly, E., Mudaly, M., Richardson, C., Barlow, D., Bomford, A., Peters, T. J., Raja, K. B., Shirali, S., Hediger, M. A., Farzaneh, F., and Simpson, R. J. (2001). An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755-1759.
99. Mena, N. P., Esparza, A. L., and Nunez, M. T. (2006). Regulation of transepithelial transport of iron by hepcidin. Biol. Res. 39, 191-193.
100. Moller, L. B., Tumer, Z., Lund, C., Petersen, C., Cole, T., Hanusch, R., Seidel, J., Jensen, L. R., and Horn, N. (2000). Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. Am. J. Hum. Genet. 66, 1211-1220.
101. Monnot, A. D., Behl, M., Ho, S., and Zheng, W. (2011). Regulation of brain copper homeostasis by the brain barrier systems: effects of Feoverload and Fe-deficiency. Toxicol. Appl. Pharmacol. 256, 249-257.
102. Monnot, A. D., Zheng, G., and Zheng, W. (2012). Mechanism of copper transport at the blood-cerebrospinal fluid barrier: influence of iron deficiency in an in vitro model. Exp. Biol. Med. (Maywood) 237, 327-333.
103. Moos, T., and Morgan, E. H. (1998). Kinetics and distribution of [59Fe125I] transferrin injected into the ventricular system of the rat. Brain Res. 790, 115-128.
104. Moos,T.,and Morgan,E. H. (2004). The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J. Neurochem. 88, 233-245.
105. Moos, T., Oates, P. S., and Morgan, E. H. (1998). Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency. J. Comp. Neurol. 398, 420-430.
106. Moos, T., Rosengren, N. T., Skjorringe, T., and Morgan, E. H. (2007). Iron trafficking inside the brain. J. Neu-rochem. 103, 1730-1740.
107. Moos, T., Skjoerringe, T., Gosk, S., and Morgan, E. H. (2006). Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J. Neurochem. 98, 1946-1958.
108. Morgan, E. H. (1977). Iron exchange between transferrin molecules mediated by phosphate compounds and other cell metabolites. Biochim. Biophys. Acta 499, 169-177.
109. Morgan, E. H. (1979). Studies on the mechanism of iron release from transferrin. Biochim. Biophys. Acta 580, 312-326.
110. Morgan, E. H. (1996). "Iron metabolismandtransport,"inHepathology-A Textbook of Liver Disease, eds D. Zakin and T. D. Bayer (Philadelphia: Saunders), 526-554.
111. Morita, H., Ikeda, S., Yamamoto, K., Morita, S., Yoshida, K., Nomoto, S., Kato, M., and Yanagisawa, N. (1995). Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann. Neurol. 37, 646-656
112. Mostad, E. J., and Prohaska, J. R. (2011). Glycosylphosphatidylinositol linked ceruloplasmin is expressed in multiple rodent organs and is lower following dietary copper deficiency. Exp. Biol. Med. (Maywood) 236, 298-308.
113. Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., and Kaplan, J. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Sci-ence 306, 2090-2093.
114. Nose, Y., Kim, B. E., and Thiele, D. J. (2006). Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab. 4, 235-244.
115. Oder,W., Grimm, G., Kollegger, H., Ferenci, P., Schneider, B., and Deecke, L. (1991). Neurological and neuropsychiatric spectrum of Wilson's disease: a prospective study of 45 cases. J. Neurol. 238, 281-287.
116. Ohgami, R. S., Campagna, D. R., McDonald, A., and Fleming, M. D. (2006). The Steap proteins are metalloreductases. Blood 108, 1388-1394.
117. Oide, T., Yoshida, K., Kaneko, K., Ohta, M., and Arima, K. (2006). Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia. Neuropathol. Appl. Neurobiol. 32, 170-176.
118. Okeda, R., Gei, S., Chen, I., Okaniwa, M., Shinomiya, M., and Matsubara, O. (1991). Menkes' kinky hair disease: morphological and immunohistochemical comparison of two autopsied patients. Acta Neu-ropathol. 81, 450-457.
119. Olivieri, S., Conti, A., Iannaccone, S., Cannistraci, C. V., Campanella, A., Barbariga, M., Codazzi, F., Pelizzoni, I., Magnani, G., Pesca, M., Franciotta, D., Cappa, S. F., and Alessio, M. (2011). Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention. J. Neurosci. 31, 18568-18577.
120. Oshiro, S., Nozawa, K., Hori, M., Zhang, C., Hashimoto, Y., Kitajima, S., and Kawamura, K. (2002). Modulation of iron regulatory protein-1 by various metals. Biochem. Biophys. Res. Commun. 290, 213-218.
121. Ostrerova-Golts, N., Petrucelli, L., Hardy, J., Lee, J. M., Farer, M., and Wolozin,B. (2000). The A53T alphasynuclein mutation increases irondependent aggregation and toxicity. J. Neurosci. 20, 6048-6054.
122. Ozcankaya, R., and Delibas, N. (2002). Malondialdehyde, superoxide dismutase, melatonin, iron, copper, and zinc blood concentrations in patients with Alzheimer disease: cross-sectional study. Croat. Med. J. 43, 28-32.
123. Patel, B. N., and David, S. (1997). A novel glycosylphosphatidylinositolanchored form of ceruloplasmin is expressed by mammalian astrocytes. J. Biol. Chem. 272, 20185-20190.
124. Pelizzoni, I., Zacchetti, D., Smith, C. P., Grohovaz, F., and Codazzi, F. (2012). Expression of divalent metal transporter 1 in primary hippocampal neurons: reconsidering its role in non-transferrin-bound iron influx. J. Neurochem. 120, 269-278.
125. Penkowa, M., Nielsen, H., Hidalgo, J., Bernth,N.,and Moos,T. (1999). Distribution of metallothionein I + II and vesicular zinc in the developing central nervous system: correlative study in the rat. J. Comp. Neurol. 412, 303-318.
126. Penland, J. G., and Prohaska, J. R. (2004). Abnormal motor function persists following recovery from perinatal copper deficiency in rats. J. Nutr. 134, 1984-1988.
127. Petris, M. J., Mercer, J. F., Culvenor, J. G., Lockhart, P., Gleeson, P. A., and Camakaris, J. (1996). Ligandregulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J. 15, 6084-6095.
128. Petris, M. J., Smith, K., Lee, J., and Thiele, D. J. (2003). Copperstimulated endocytosis and degradation of the human copper transporter, hCtr1. J. Biol. Chem. 278, 9639-9646.
129. Pinilla-Tenas, J. J., Sparkman, B. K., Shawki, A., Illing, A. C., Mitchell, C. J., Zhao, N., Liuzzi, J. P., Cousins, R. J., Knutson, M. D., and Mackenzie, B. (2011). Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron.Am. J. Physiol. Cell Physiol. 301, C862-C871.
130. Prodan, C. I., Bottomley, S. S., Holland, N. R., and Lind, S. E. (2006). Relapsing hypocupraemic myelopathy requiring high-dose oral copper replacement. J. Neurol. Neurosurg. Psychiatr. 77, 1092-1093.
131. Prohaska, J. R. (1989). Effect of diet on milk copper, and iron content of normal, and heterozygous brindled mice. Nutr. Res. 9, 353-356.
132. Prohaska, J. R., and Brokate, B. (2001). Dietary copper deficiency alters protein levels of rat dopamine beta-monooxygenase and tyrosine monooxygenase. Exp. Biol. Med. (Maywood) 226, 199-207.
133. Prohaska, J. R., and Gybina, A. A. (2005). Rat brain iron concentration is lower following perinatal copper deficiency. J. Neurochem. 93, 698-705.
134. Prohaska, J. R., and Wells, W. W. (1974). Copper deficiency in the developing rat brain: a possible model for Menkes' steely-hair disease. J. Neu-rochem. 23, 91-98.
135. Puig, S., and Thiele, D. J. (2002). Molecular mechanisms of copper uptake and distribution. Curr. Opin. Chem. Biol. 6, 171-180.
136. Pyatskowit, J. W., and Prohaska, J. R. (2008). Copper deficient rats and mice both develop anemia but only rats have lower plasma and brain iron levels. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 147, 316-323.
137. Qian, Y., Tiffany-Castiglioni, E., Welsh, J., and Harris, E. D. (1998). Copper efflux from murine microvascular cells requires expression of the menkes disease Cu-ATPase. J. Nutr. 128, 1276-1282.
138. Rae, T. D., Schmidt, P. J., Pufahl, R. A., Culotta, V. C., and O'Halloran, T. V. (1999). Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284, 805-808.
139. Rivera-Mancia, S., Perez-Neri, I., Rios, C., Tristan-Lopez, L., RiveraEspinosa, L., and Montes, S. (2010). The transition metals copper and iron in neurodegenerative diseases. Chem. Biol. Interact. 186, 184-199.
140. Roelofsen,H.,Wolters,H.,Van Luyn, M. J., Miura, N., Kuipers, F., and Vonk, R. J. (2000). Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology 119, 782-793.
141. Roth, J. A., Singleton, S., Feng, J., Garrick, M., and Paradkar, P. N. (2010). Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1. J. Neurochem. 113, 454-464.
142. Rouault, T. A. (2001). Iron on the brain. Nat. Genet. 28, 299-300.
143. Rouault, T. A., Zhang, D. L., and Jeong, S. Y. (2009). Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab. Brain Dis. 24, 673-684.
144. Saito, T., Okabe, M., Hosokawa, T., Kurasaki, M., Hata, A., Endo, F., Nagano, K., Matsuda, I., Urakami, K., and Saito, K. (1999). Immunohistochemical determination of the Wilson copper-transporting P-type ATPase in the brain tissues of the rat. Neurosci. Lett. 266, 13-16.
145. Salazar, J., Mena, N., Hunot, S., Prigent, A., varez-Fischer, D., Arredondo, M., Duyckaerts, C., Sazdovitch,V., Zhao, L., Garrick, L. M., Nunez, M. T., Garrick, M. D., Raisman-Vozari, R., and Hirsch, E. C. (2008). Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A. 105, 18578-18583.
146. Sastry, S., and Arendash, G. W. (1995). Time-dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. Neu-roscience 67, 649-666.
147. Schlief, M. L., and Gitlin, J. D. (2006). Copper homeostasis in the CNS: a novel link between the NMDA receptor and copper homeostasis in the hippocampus. Mol. Neurobiol. 33, 81-90.
148. Sharp, P. (2004). The molecular basis of copper and iron interactions. Proc. Nutr. Soc. 63, 563-569.
149. Shayeghi, M., Latunde-Dada, G. O., Oakhill, J. S., Laftah,A. H., Takeuchi K., Halliday, N., Khan, Y., Warley, A., McCann, F. E., Hider, R. C., Frazer, D. M., Anderson, G. J., Vulpe, C. D., Simpson, R. J., and McKie,A. T. (2005). Identification of an intestinal heme transporter. Cell 122, 789-801.
150. Siddappa,A. M., Georgieff, M. K.,Wewerka, S., Worwa, C., Nelson, C. A., and Deregnier, R. A. (2004). Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers. Pediatr. Res. 55, 1034-1041.
151. Sofic, E., Riederer, P., Heinsen, H., Beckmann, H., Reynolds, G. P., Hebenstreit, G., and Youdim, M. B. (1988). Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J. Neural Transm. 74, 199-205.
152. Song, M. O., Li, J., and Freedman, J. H. (2009). Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol. Genomics 38, 386-401.
153. Squitti, R., Barbati, G., Rossi, L., Ventriglia, M., Dal, F. G., Cesaretti, S., Moffa, F., Caridi, I., Cassetta, E., Pasqualetti, P., Calabrese, L., Lupoi, D., and Rossini, P. M. (2006). Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau. Neurol-ogy 67, 76-82.
154. Tao, T. Y., and Gitlin, J. D. (2003). Hepatic copper metabolism: insights from genetic disease. Hepatology 37, 1241-1247.
155. Tarohda, T., Ishida, Y., Kawai, K., Yamamoto, M., and Amano, R. (2005). Regional distributions of manganese, iron, copper, and zinc in the brains of 6-hydroxydopamineinduced parkinsonian rats. Anal. Bioanal. Chem. 383, 224-234.
156. Tennant, J., Stansfield, M., Yamaji, S., Srai, S. K., and Sharp, P. (2002). Effects of copper on the expression of metal transporters in human intestinal Caco-2 cells. FEBS Lett. 527, 239-244.
157. Treiber, C., Simons, A., Strauss, M., Hafner, M., Cappai, R., Bayer, T. A., and Multhaup, G. (2004). Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease. J. Biol. Chem. 279, 51958-51964.
158. Uitti, R. J., Rajput, A. H., Rozdilsky, B., Bickis, M., Wollin, T., and Yuen, W. K. (1989). Regional metal concentrations in Parkinson's disease, other chronic neurological diseases, and control brains. Can. J. Neurol. Sci. 16, 310-314.
159. Umbreit, J. (2005). Iron deficiency: a concise review. Am. J. Hematol. 78, 225-231.
160. van den Berghe, P. V., and Klomp, L. W. (2010). Posttranslational regulation of copper transporters. J. Biol. Inorg. Chem. 15, 37-46.
161. Varada, K. R., Harper, R. G., and Wapnir, R. A. (1993). Development of copper intestinal absorption in the rat. Biochem. Med. Metab. Biol. 50, 277-283.
162. Vural, H., Demirin, H., Kara, Y., Eren, I., and Delibas, N. (2010). Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer's disease. J. Trace Elem. Med. Biol. 24, 169-173.
163. Wang, J., and Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochem. J. 434, 365-381.
164. Wang,X.,Li,G. J.,and Zheng,W. (2008). Efflux of iron from the cerebrospinal fluid to the blood at the blood-CSF barrier: effect of manganese exposure. Exp. Biol. Med. (Maywood) 233, 1561-1571.
165. West, A. R., and Oates, P. S. (2008). Mechanisms of heme iron absorption: current questions and controversies. World J. Gastroenterol. 14, 4101-4110.
166. Wypijewska, A., Galazka-Friedman, J., Bauminger, E. R., Wszolek, Z. K., Schweitzer,K. J., Dickson,D. W.,Jaklewicz, A., Elbaum, D., and Friedman, A. (2010). Iron and reactive oxygen species activity in parkinsonian substantia nigra. Parkinsonism Relat. Disord. 16, 329-333.
167. Xie, L., and Collins, J. F. (2011). Transcriptional regulation of the Menkes copper ATPase (Atp7a) gene by hypoxia-inducible factor (HIF2{alpha}) in intestinal epithelial cells. Am. J. Physiol. Cell Physiol. 300, C1298-C1305.
168. Yang, W. M., Jung, K. J., Lee, M. O., Lee, Y. S., Lee, Y. H., Nakagawa, S., Niwa, M., Cho, S. S., and Kim, D. W. (2011). Transient expression of iron transport proteins in the capillary of the developing rat brain. Cell. Mol. Neurobiol. 31, 93-99.
169. Yoshimura, N., Kida, K., Usutani, S., and Nishimura, M. (1995). Histochemical localization of copper in various organs of brindled mice after copper therapy. Pathol. Int. 45, 10-18.
170. Zheng, G., Chen, J., and Zheng, W. (2012). Relative contribution of CTR1 and DMT1 in copper transport by the blood-CSF barrier: implication in manganese-induced neurotoxicity. Toxicol. Appl. Phar-macol. 260, 285-293.
171. Zhou, B., Westaway, S. K., Levinson, B., Johnson, M. A., Gitschier, J., and Hayflick, S. J. (2001). A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345-349.