Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease

Journal of Neurochemistry

Volumn 113, Issue 6, 2010, Pages 1387-1402

  Johnstone, Daniel ^a   Milward, Elizabeth A ^a  

^a HUNTER MEDICAL RESEARCH INSTITUTE   (Australia)

Author keywords

Brain; Genetics; Hemochromatosis; Iron; Neurodegenerative disease

Indexed keywords

CD71 ANTIGEN; FERRITIN; FERROPORTIN; HEPCIDIN; HFE PROTEIN; IRON; IRON REGULATORY FACTOR; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; TRANSFERRIN; TRANSFERRIN RECEPTOR 2;

BLOOD BRAIN BARRIER; BRAIN DISEASE; BRAIN HEALTH; BRAIN PROTECTION; CATARACT; GENE EXPRESSION; GENE MUTATION; GENETIC DISORDER; GENETIC POLYMORPHISM; GENETIC PROCEDURES; GENETIC TRANSCRIPTION; HEALTH; HOMEOSTASIS; HUMAN; HYPERFERRITINEMIA; IRON THERAPY; LOSS OF FUNCTION MUTATION; MOLECULAR GENETICS; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION; NEUROPATHOLOGY; NONHUMAN; PRIORITY JOURNAL; REVIEW; TRANSFERRIN DEFICIENCY;

ANIMALS; BRAIN; BRAIN DISEASES; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION TO DISEASE; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IRON; MEMBRANE PROTEINS; MOLECULAR BIOLOGY; POLYMORPHISM, GENETIC;

EID: 77953110019     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/j.1471-4159.2010.06697.x     Document Type: Review

References (180)

1. Adams P. C., Reboussin D. M., Barton J. C. et al. (2005) Hemochromatosis and iron-overload screening in a racially diverse population. N. Engl. J. Med. 352, 1769 1778.
2. Aisen P., Enns C. Wessling-Resnick M. (2001) Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol. 33, 940 959.
3. Allen K. J., Gurrin L. C., Constantine C. C. et al. (2008) Iron-overload-related disease in HFE hereditary hemochromatosis. N. Engl. J. Med. 358, 221 230.
4. Andrews N. C. (1999) Disorders of iron metabolism. N. Engl. J. Med. 341, 1986 1995.
5. Angelini L., Nardocci N., Rumi V., Zorzi C., Strada L. Savoiardo M. (1992) Hallervorden-Spatz disease: clinical and MRI study of 11 cases diagnosed in life. J. Neurol. 239, 417 425.
6. Antunes F., Cadenas E. Brunk U. T. (2001) Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture. Biochem. J. 356, 549 555.
7. Atamna H., Killilea D. W., Killilea A. N. Ames B. N. (2002) Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc. Natl Acad. Sci. USA 99, 14807 14812.
8. Ayonrinde O. T., Milward E. A., Chua A. C., Trinder D. Olynyk J. K. (2008) Clinical perspectives on hereditary hemochromatosis. Crit. Rev. Clin. Lab. Sci. 45, 451 484.
9. Bartzokis G. Tishler T. A. (2000) MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease. Cell. Mol. Biol. (Noisy-le-grand) 46, 821 833.
10. Bartzokis G., Beckson M., Hance D. B., Marx P., Foster J. A. Marder S. R. (1997) MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn. Reson. Imaging 15, 29 35.
11. Bartzokis G., Lu P. H., Tishler T. A. et al. (2010) Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men. J. Alzheimers Dis. (Epub ahead of print 2010/02/19).
12. Bassi M. T., Manzoni M., Monti E., Pizzo M. T., Ballabio A. Borsani G. (2000) Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am. J. Hum. Genet. 67, 1110 1120.
13. Bastin J. M., Jones M., O'Callaghan C. A., Schimanski L., Mason D. Y. Townsend A. R. (1998) Kupffer cell staining by an HFE-specific monoclonal antibody: implications for hereditary haemochromatosis. Br. J. Haematol. 103, 931 941.
14. Beard J. L. Connor J. R. (2003) Iron status and neural functioning. Annu. Rev. Nutr. 23, 41 58.
15. Ben-Shachar D., Eshel G., Finberg J. P. Youdim M. B. (1991) The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J. Neurochem. 56, 1441 1444.
16. Berg D. Youdim M. B. (2006) Role of iron in neurodegenerative disorders. Top. Magn. Reson. Imaging 17, 5 17.
17. Berg D., Hoggenmuller U., Hofmann E., Fischer R., Kraus M., Scheurlen M. Becker G. (2000) The basal ganglia in haemochromatosis. Neuroradiology 42, 9 13.
18. Beutler E., Gelbart T., Lee P., Trevino R., Fernandez M. A. Fairbanks V. F. (2000) Molecular characterization of a case of atransferrinemia. Blood 96, 4071 4074.
19. de Bie P., Muller P., Wijmenga C. Klomp L. W. (2007) Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J. Med. Genet. 44, 673 688.
20. Billi de Catabbi S. C., Faletti A., Fuentes F., San Martin de Viale L. C. Cochon A. C. (2005) Hepatic arachidonic acid metabolism is disrupted after hexachlorobenzene treatment. Toxicol. Appl. Pharmacol. 204, 187 195.
21. Blacker D., Bertram L., Saunders A. J. et al. (2003) Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum. Mol. Genet. 12, 23 32.
22. Bonneau D., Winter-Fuseau I., Loiseau M. N., Amati P., Berthier M., Oriot D. Beaumont C. (1995) Bilateral cataract and high serum ferritin: a new dominant genetic disorder? J. Med. Genet. 32, 778 779.
23. Bradbury M. W. (1997) Transport of iron in the blood-brain-cerebrospinal fluid system. J. Neurochem. 69, 443 454.
24. Bridle K. R., Frazer D. M., Wilkins S. J. et al. (2003) Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361, 669 673.
25. Brunk U. T. Terman A. (2002) Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic. Biol. Med. 33, 611 619.
26. Burdo J. R. Connor J. R. (2003) Brain iron uptake and homeostatic mechanisms: an overview. Biometals 16, 63 75.
27. Burn J. Chinnery P. F. (2006) Neuroferritinopathy. Semin. Pediatr. Neurol. 13, 176 181.
28. Carri M. T., Ferri A., Cozzolino M., Calabrese L. Rotilio G. (2003) Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Res. Bull. 61, 365 374.
29. Chang Y. Z., Qian Z. M., Wang K. et al. (2005) Effects of development and iron status on ceruloplasmin expression in rat brain. J. Cell. Physiol. 204, 623 631.
30. Chua A. C., Graham R. M., Trinder D. Olynyk J. K. (2007) The regulation of cellular iron metabolism. Crit. Rev. Clin. Lab. Sci. 44, 413 459.
31. Clardy S. L., Wang X., Zhao W., Liu W., Chase G. A., Beard J. L., True Felt B. Connor J. R. (2006) Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain. J. Neural Transm. Suppl. 71, 173 196.
32. Collingwood J. F., Chong R. K., Kasama T. et al. (2008) Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material. J. Alzheimers Dis. 14, 235 245.
33. Collins J. S., Perry R. T., Watson B., Jr. et al. (2000) Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative. Am. J. Med. Genet. 96, 823 830.
34. Connor J. R., Milward E. A., Moalem S., Sampietro M., Boyer P., Percy M. E., Vergani C., Scott R. J. Chorney M. (2001) Is hemochromatosis a risk factor for Alzheimer's disease? J. Alzheimers Dis. 3, 471 477.
35. Cooperman S. S., Meyron-Holtz E. G., Olivierre-Wilson H., Ghosh M. C., McConnell J. P. Rouault T. A. (2005) Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood 106, 1084 1091.
36. Crompton D. E., Chinnery P. F., Fey C. et al. (2002) Neuroferritinopathy: a window on the role of iron in neurodegeneration. Blood Cells Mol. Dis. 29, 522 531.
37. Crooks C. J., West J., Solaymani-Dodaran M. Card T. R. (2009) The epidemiology of haemochromatosis: a population-based study. Aliment. Pharmacol. Ther. 29, 183 192.
38. Curtis A. R., Fey C., Morris C. M. et al. (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet. 28, 350 354.
39. De Domenico I., Ward D. M., di Patti M. C., Jeong S. Y., David S., Musci G. Kaplan J. (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 26, 2823 2831.
40. Demarquay G., Thobois S., Latour P. Broussolle E. (2006) Hereditary hemochromatosis and movement disorders: the still controversial relationship. Response to Russo et al. in J Neurol (2004) 251:849-852. J. Neurol. 253, 261 262.
41. Dexter D. T., Jenner P., Schapira A. H. Marsden C. D. (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group. Ann. Neurol. 32 (Suppl S94 S100.
42. Dickinson T. K. Connor J. R. (1994) Histological analysis of selected brain regions of hypotransferrinemic mice. Brain Res. 635, 169 178.
43. Dong X. P., Cheng X., Mills E., Delling M., Wang F., Kurz T. Xu H. (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455, 992 996.
44. Dornelles A. S., Garcia V. A., de Lima M. N., Vedana G., Alcalde L. A., Bogo M. R. Schroder N. (2010) mRNA expression of proteins involved in iron homeostasis in brain regions is altered by age and by iron overloading in the neonatal period. Neurochem. Res. 35, 564 571.
45. Ellervik C., Birgens H., Tybjaerg-Hansen A. Nordestgaard B. G. (2007) Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology 46, 1071 1080.
46. Eroglu Y. Byrne W. J. (2009) Hepatic encephalopathy. Emerg. Med. Clin. North Am. 27, 401 414.
47. Fasano A., Bentivoglio A. R. Colosimo C. (2007) Movement disorder due to aceruloplasminemia and incorrect diagnosis of hereditary hemochromatosis. J. Neurol. 254, 113 114.
48. Ferreira C., Bucchini D., Martin M. E., Levi S., Arosio P., Grandchamp B. Beaumont C. (2000) Early embryonic lethality of H ferritin gene deletion in mice. J. Biol. Chem. 275, 3021 3024.
49. Fredriksson A., Schroder N., Eriksson P., Izquierdo I. Archer T. (1999) Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice. Toxicol. Appl. Pharmacol. 159, 25 30.
50. Galvin J. E., Giasson B., Hurtig H. I., Lee V. M. Trojanowski J. Q. (2000) Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am. J. Pathol. 157, 361 368.
51. Galy B., Ferring D., Minana B., Bell O., Janser H. G., Muckenthaler M., Schumann K. Hentze M. W. (2005) Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood 106, 2580 2589.
52. Galy B., Holter S. M., Klopstock T., Ferring D., Becker L., Kaden S., Wurst W., Grone H. J. Hentze M. W. (2006) Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat. Genet. 38, 967 969.
53. Gao J., Chen J., Kramer M., Tsukamoto H., Zhang A. S. Enns C. A. (2009) Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 9, 217 227.
54. Girelli D., Olivieri O., De Franceschi L., Corrocher R., Bergamaschi G. Cazzola M. (1995) A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract. Br. J. Haematol. 90, 931 934.
55. Gochee P. A., Powell L. W., Cullen D. J., Du Sart D., Rossi E. Olynyk J. K. (2002) A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 122, 646 651.
56. Golub M. S., Germann S. L., Araiza R. S., Reader J. R., Griffey S. M. Lloyd K. C. (2005) Movement disorders in the Hfe knockout mouse. Nutr. Neurosci. 8, 239 244.
57. Goodall E. F., Greenway M. J., van Marion I., Carroll C. B., Hardiman O. Morrison K. E. (2005) Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS. Neurology 65, 934 937.
58. Gregory A., Westaway S. K., Holm I. E. et al. (2008) Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71, 1402 1409.
59. Gregory A., Polster B. J. Hayflick S. J. (2009) Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J. Med. Genet. 46, 73 80.
60. Gunshin H., Allerson C. R., Polycarpou-Schwarz M. et al. (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett. 509, 309 316.
61. Hanninen M. M., Haapasalo J., Haapasalo H., Fleming R. E., Britton R. S., Bacon B. R. Parkkila S. (2009) Expression of iron-related genes in human brain and brain tumors. BMC Neurosci. 10, 36.
62. Harvey R. J., Summerfield J. A. Fox N. C. (1997) Dementia associated with haemochromatosis. A report of two cases. Eur. J. Neurol. 4, 318 322.
63. Hayflick S. J., Westaway S. K., Levinson B., Zhou B., Johnson M. A., Ching K. H. Gitschier J. (2003) Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N. Engl. J. Med. 348, 33 40.
64. Hellman N. E. Gitlin J. D. (2002) Ceruloplasmin metabolism and function. Annu. Rev. Nutr. 22, 439 458.
65. Hentze M. W. Kuhn L. C. (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc. Natl Acad. Sci. USA 93, 8175 8182.
66. Higgins J. J., Patterson M. C., Papadopoulos N. M., Brady R. O., Pentchev P. G. Barton N. W. (1992) Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology 42, 194 198.
67. Honda K., Casadesus G., Petersen R. B., Perry G. Smith M. A. (2004) Oxidative stress and redox-active iron in Alzheimer's disease. Ann. N Y Acad. Sci. 1012, 179 182. (Pubitemid 38453525)
68. House M. J., St Pierre T. G., Kowdley K. V. et al. (2007) Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from Alzheimer's disease patients. Magn. Reson. Med. 57, 172 180.
69. House M. J., St. Pierre T. G., Milward E. A., Bruce D. G. Olynyk J. K. (2010) Relationship between brain R2 and liver and serum iron concentrations in elderly men. Magn. Reson. Med. 63, 275 281.
70. Jeong S. Y., Rathore K. I., Schulz K., Ponka P., Arosio P. David S. (2009) Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 29, 610 619.
71. Kakhlon O. Cabantchik Z. I. (2002) The labile iron pool: characterization, measurement, and participation in cellular processes(1). Free Radic. Biol. Med. 33, 1037 1046.
72. Kakhlon O., Gruenbaum Y. Cabantchik Z. I. (2001) Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells. Blood 97, 2863 2871.
73. Karimi M., Khanlari M. Rachmilewitz E. A. (2008) Cerebrovascular accident in beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI). Am. J. Hematol. 83, 77 79.
74. Kato J., Fujikawa K., Kanda M. et al. (2001) A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am. J. Hum. Genet. 69, 191 197.
75. Kaur D., Rajagopalan S., Chinta S., Kumar J., Di Monte D., Cherny R. A. Andersen J. K. (2007) Chronic ferritin expression within murine dopaminergic midbrain neurons results in a progressive age-related neurodegeneration. Brain Res. 1140, 188 194.
76. Ke Y., Chang Y. Z., Duan X. L., Du J. R., Zhu L., Wang K., Yang X. D., Ho K. P. Qian Z. M. (2005) Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiol. Aging 26, 739 748.
77. Ke Y., Ho K., Du J. et al. (2006) Role of soluble ceruloplasmin in iron uptake by midbrain and hippocampus neurons. J. Cell. Biochem. 98, 912 919.
78. Kehoe P., Wavrant-De Vrieze F., Crook R. et al. (1999) A full genome scan for late onset Alzheimer's disease. Hum. Mol. Genet. 8, 237 245.
79. Kidane T. Z., Sauble E. Linder M. C. (2006) Release of iron from ferritin requires lysosomal activity. Am. J. Physiol. Cell Physiol. 291, C445 C455.
80. Knutson M. D., Levy J. E., Andrews N. C. Wessling-Resnick M. (2001) Expression of stimulator of Fe transport is not enhanced in Hfe knockout mice. J. Nutr. 131, 1459 1464.
81. Kono S. Miyajima H. (2006) Molecular and pathological basis of aceruloplasminemia. Biol. Res. 39, 15 23.
82. Kruszewski M. (2003) Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat. Res. 531, 81 92.
83. Kuo Y. M., Duncan J. L., Westaway S. K., Yang H., Nune G., Xu E. Y., Hayflick S. J. Gitschier J. (2005) Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum. Mol. Genet. 14, 49 57.
84. Kurz T., Terman A., Gustafsson B. Brunk U. T. (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem. Cell Biol. 129, 389 406.
85. LaVaute T., Smith S., Cooperman S. et al. (2001) Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat. Genet. 27, 209 214.
86. Lee D. W. Andersen J. K. (2010) Iron elevations in the aging Parkinsonian brain: a consequence of impaired iron homeostasis? J. Neurochem. 112, 332 339.
87. Lesuisse E., Santos R., Matzanke B. F., Knight S. A., Camadro J. M. Dancis A. (2003) Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum. Mol. Genet. 12, 879 889.
88. Levenson C. W. Tassabehji N. M. (2004) Iron and ageing: an introduction to iron regulatory mechanisms. Ageing Res. Rev. 3, 251 263.
89. LeVine S. M. (1997) Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res. 760, 298 303.
90. Levy J. E., Jin O., Fujiwara Y., Kuo F. Andrews N. C. (1999) Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396 399.
91. Lin L., Goldberg Y. P. Ganz T. (2005) Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 106, 2884 2889.
92. Linert W., Herlinger E., Jameson R. F., Kienzl E., Jellinger K. Youdim M. B. (1996) Dopamine, 6-hydroxydopamine, iron, and dioxygen-their mutual interactions and possible implication in the development of Parkinson's disease. Biochim. Biophys. Acta 1316, 160 168.
93. Liu G., Men P., Harris P. L., Rolston R. K., Perry G. Smith M. A. (2006) Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci. Lett. 406, 189 193.
94. Liu M., Xiao D. S. Qian Z. M. (2007) Identification of transcriptionally regulated genes in response to cellular iron availability in rat hippocampus. Mol. Cell. Biochem. 300, 139 147.
95. Loeffler D. A., Connor J. R., Juneau P. L., Snyder B. S., Kanaley L., DeMaggio A. J., Nguyen H., Brickman C. M. LeWitt P. A. (1995) Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions. J. Neurochem. 65, 710 724.
96. Lucato L. T., Otaduy M. C., Barbosa E. R., Machado A. A., McKinney A., Bacheschi L. A., Scaff M., Cerri G. G. Leite C. C. (2005) Proton MR spectroscopy in Wilson disease: analysis of 36 cases. AJNR Am. J. Neuroradiol. 26, 1066 1071.
97. Lumsden A. L., Henshall T. L., Dayan S., Lardelli M. T. Richards R. I. (2007) Huntingtin-deficient zebrafish exhibit defects in iron utilization and development. Hum. Mol. Genet. 16, 1905 1920.
98. Maaroufi K., Ammari M., Jeljeli M., Roy V., Sakly M. Abdelmelek H. (2009) Impairment of emotional behavior and spatial learning in adult Wistar rats by ferrous sulfate. Physiol. Behav. 96, 343 349.
99. Manfre L., Giarratano E., Maggio A., Banco A., Vaccaro G. Lagalla R. (1999) MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease. AJR Am. J. Roentgenol. 173, 1477 1480.
100. Marques F., Falcao A. M., Sousa J. C., Coppola G., Geschwind D., Sousa N., Correia-Neves M. Palha J. A. (2009) Altered iron metabolism is part of the choroid plexus response to peripheral inflammation. Endocrinology 150, 2822 2828.
101. Martin W. R., Wieler M. Gee M. (2008) Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 70, 1411 1417.
102. Mattson M. P. (2004) Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders. Ann. N Y Acad. Sci. 1012, 37 50.
103. McCune C. A., Ravine D., Carter K., Jackson H. A., Hutton D., Hedderich J., Krawczak M. Worwood M. (2006) Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients. Gut 55, 554 562.
104. McNeill A., Pandolfo M., Kuhn J., Shang H. Miyajima H. (2008a) The neurological presentation of ceruloplasmin gene mutations. Eur. Neurol. 60, 200 205.
105. McNeill A., Birchall D., Hayflick S. J., Gregory A., Schenk J. F., Zimmerman E. A., Shang H., Miyajima H. Chinnery P. F. (2008b) T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 70, 1614 1619.
106. Michaeli S., Oz G., Sorce D. J., Garwood M., Ugurbil K., Majestic S. Tuite P. (2007) Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts. Mov. Disord. 22, 334 340.
107. Milward E. A., Baines S. K., Knuiman M. W., Bartholomew H. C., Divitini M. L., Ravine D. G., Bruce D. G. Olynyk J. K. (2008) Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations. Mayo Clin. Proc. 83, 543 549.
108. Miyajima H., Nishimura Y., Mizoguchi K., Sakamoto M., Shimizu T. Honda N. (1987) Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37, 761 767.
109. Miyajima H., Takahashi Y., Kamata T., Shimizu H., Sakai N. Gitlin J. D. (1997) Use of desferrioxamine in the treatment of aceruloplasminemia. Ann. Neurol. 41, 404 407.
110. Monastero R., Monastero G., Ciaccio C., Padovani A. Camarda R. (2000) Cognitive deficits in beta-thalassemia major. Acta Neurol. Scand. 102, 162 168.
111. Moos T. Morgan E. H. (2004) The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann. N Y Acad. Sci. 1012, 14 26.
112. Moos T. Rosengren Nielsen T. (2006) Ferroportin in the postnatal rat brain: implications for axonal transport and neuronal export of iron. Semin. Pediatr. Neurol. 13, 149 157.
113. Moos T., Oates P. S. Morgan E. H. (1999) Iron-independent neuronal expression of transferrin receptor mRNA in the rat. Brain Res. Mol. Brain Res. 72, 231 234.
114. Moos T., Trinder D. Morgan E. H. (2000) Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and beta2-microglobulin deficient mouse brain. Cell. Mol. Biol. (Noisy-le-grand) 46, 549 561.
115. Moos T., Oates P. S. Morgan E. H. (2001) Expression of transferrin mRNA in rat oligodendrocytes is iron-independent and changes with increasing age. Nutr. Neurosci. 4, 15 23.
116. Moos T., Rosengren Nielsen T., Skjorringe T. Morgan E. H. (2007) Iron trafficking inside the brain. J. Neurochem. 103, 1730 1740.
117. Morgan N. V., Westaway S. K., Morton J. E. et al. (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 38, 752 754.
118. Mubaidin A., Roberts E., Hampshire D. et al. (2003) Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum. J. Med. Genet. 40, 543 546.
119. Muckenthaler M. U., Galy B. Hentze M. W. (2008) Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu. Rev. Nutr. 28, 197 213.
120. Mukhopadhyay C. K., Attieh Z. K. Fox P. L. (1998) Role of ceruloplasmin in cellular iron uptake. Science 279, 714 717.
121. Nakajima O., Takahashi S., Harigae H., Furuyama K., Hayashi N., Sassa S. Yamamoto M. (1999) Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload. EMBO J. 18, 6282 6289.
122. Nemeth E., Tuttle M. S., Powelson J., Vaughn M. B., Donovan A., Ward D. M., Ganz T. Kaplan J. (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090 2093.
123. Nemeth E., Roetto A., Garozzo G., Ganz T. Camaschella C. (2005) Hepcidin is decreased in TFR2 hemochromatosis. Blood 105, 1803 1806.
124. Neumann M., Adler S., Schluter O., Kremmer E., Benecke R. Kretzschmar H. A. (2000) Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. Acta Neuropathol. 100, 568 574.
125. Nicolas G., Chauvet C., Viatte L., Danan J. L., Bigard X., Devaux I., Beaumont C., Kahn A. Vaulont S. (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110, 1037 1044.
126. Niederau C., Fischer R., Purschel A., Stremmel W., Haussinger D. Strohmeyer G. (1996) Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110, 1107 1119.
127. Nielsen J. E., Jensen L. N. Krabbe K. (1995) Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome. J. Neurol. Neurosurg. Psychiatry 59, 318 321.
128. Pandolfo M. Pastore A. (2009) The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J. Neurol. 256 (Suppl 1 9 17.
129. Papanikolaou G., Samuels M. E., Ludwig E. H. et al. (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36, 77 82.
130. Papanikolaou G., Tzilianos M., Christakis J. I. et al. (2005) Hepcidin in iron overload disorders. Blood 105, 4103 4105.
131. Park S., Gakh O., Mooney S. M. Isaya G. (2002) The ferroxidase activity of yeast frataxin. J. Biol. Chem. 277, 38589 38595.
132. Patel B. N., Dunn R. J., Jeong S. Y., Zhu Q., Julien J. P. David S. (2002) Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J. Neurosci. 22, 6578 6586.
133. Pearce J. M. (2006) Neurodegeneration with brain iron accumulation: a cautionary tale. Eur. Neurol. 56, 66 68.
134. Pellecchia M. T., Valente E. M., Cif L. et al. (2005) The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology 64, 1810 1812. (Pubitemid 40695829)
135. Pigeon C., Ilyin G., Courselaud B., Leroyer P., Turlin B., Brissot P. Loreal O. (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 276, 7811 7819.
136. Pinero D. J., Li N. Q., Connor J. R. Beard J. L. (2000) Variations in dietary iron alter brain iron metabolism in developing rats. J. Nutr. 130, 254 263.
137. Ponka P. (2002) Rare causes of hereditary iron overload. Semin. Hematol. 39, 249 262.
138. Powell L. W., Dixon J. L., Ramm G. A. et al. (2006) Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch. Intern. Med. 166, 294 301.
139. Puccio H., Simon D., Cossee M. et al. (2001) Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat. Genet. 27, 181 186.
140. Pulliam J. F., Jennings C. D., Kryscio R. J., Davis D. G., Wilson D., Montine T. J., Schmitt F. A. Markesbery W. R. (2003) Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with APOE. Am. J. Med. Genet. B Neuropsychiatr. Genet. 119B, 48 53.
141. Qian Z. M., Chang Y. Z., Zhu L. et al. (2007) Development and iron-dependent expression of hephaestin in different brain regions of rats. J. Cell. Biochem. 102, 1225 1233.
142. Robson K. J., Lehmann D. J., Wimhurst V. L., Livesey K. J., Combrinck M., Merryweather-Clarke A. T., Warden D. R. Smith A. D. (2004) Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease. J. Med. Genet. 41, 261 265.
143. Rodriguez Martinez A., Niemela O. Parkkila S. (2004) Hepatic and extrahepatic expression of the new iron regulatory protein hemojuvelin. Haematologica 89, 1441 1445.
144. Rodriguez A., Pan P. Parkkila S. (2007) Expression studies of neogenin and its ligand hemojuvelin in mouse tissues. J. Histochem. Cytochem. 55, 85 96.
145. Rotig A., de Lonlay P., Chretien D., Foury F., Koenig M., Sidi D., Munnich A. Rustin P. (1997) Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17, 215 217.
146. Rottkamp C. A., Raina A. K., Zhu X., Gaier E., Bush A. I., Atwood C. S., Chevion M., Perry G. Smith M. A. (2001) Redox-active iron mediates amyloid-beta toxicity. Free Radic. Biol. Med. 30, 447 450.
147. Rouault T. A. (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol. 2, 406 414.
148. Rouault T. A. Cooperman S. (2006) Brain iron metabolism. Semin. Pediatr. Neurol. 13, 142 148.
149. Rouault T. Klausner R. (1997) Regulation of iron metabolism in eukaryotes. Curr. Top. Cell. Regul. 35, 1 19.
150. Rouault T. A., Zhang D. L. Jeong S. Y. (2009) Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab. Brain Dis. 24, 673 684.
151. Russo N., Edwards M., Andrews T., O'Brien M. Bhatia K. P. (2004) Hereditary haemochromatosis is unlikely to cause movement disorders-a critical review. J. Neurol. 251, 849 852.
152. Rutgers M. P., Pielen A. Gille M. (2007) Chronic cerebellar ataxia and hereditary hemochromatosis: causal or coincidental association? J. Neurol. 254, 1296 1297.
153. Schmidt P. J., Toran P. T., Giannetti A. M., Bjorkman P. J. Andrews N. C. (2008) The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 7, 205 214.
154. Schoenfeld R. A., Napoli E., Wong A. et al. (2005) Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum. Mol. Genet. 14, 3787 3799.
155. Sheftel A. D., Zhang A. S., Brown C., Shirihai O. S. Ponka P. (2007) Direct interorganellar transfer of iron from endosome to mitochondrion. Blood 110, 125 132.
156. Smith M. A., Harris P. L., Sayre L. M. Perry G. (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94, 9866 9868.
157. Sobotka T. J., Whittaker P., Sobotka J. M., Brodie R. E., Quander D. Y., Robl M., Bryant M. Barton C. N. (1996) Neurobehavioral dysfunctions associated with dietary iron overload. Physiol. Behav. 59, 213 219. (Pubitemid 26075099)
158. Sun M., Goldin E., Stahl S. et al. (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum. Mol. Genet. 9, 2471 2478.
159. Sutedja N. A., Sinke R. J., Van Vught P. W. et al. (2007) The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population. Arch. Neurol. 64, 63 67.
160. Takahashi Y., Miyajima H., Shirabe S., Nagataki S., Suenaga A. Gitlin J. D. (1996) Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum. Mol. Genet. 5, 81 84.
161. Tellez-Nagel I., Rapin I., Iwamoto T., Johnson A. B., Norton W. T. Nitowsky H. (1976) Mucolipidosis IV. Clinical, ultrastructural, histochemical, and chemical studies of a case, including a brain biopsy. Arch. Neurol. 33, 828 835.
162. Terman A. Brunk U. T. (2004) Lipofuscin. Int. J. Biochem. Cell Biol. 36, 1400 1404.
163. Terman A., Gustafsson B. Brunk U. T. (2007) Autophagy, organelles and ageing. J. Pathol. 211, 134 143.
164. Thompson K., Menzies S., Muckenthaler M., Torti F. M., Wood T., Torti S. V., Hentze M. W., Beard J. Connor J. (2003) Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress. J. Neurosci. Res. 71, 46 63.
165. Vidal R., Miravalle L., Gao X. et al. (2008) Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice. J. Neurosci. 28, 60 67.
166. Vonk W. I. Klomp L. W. (2008) Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis. Biochem. Soc. Trans. 36, 1322 1328.
167. Wallace D. F., Summerville L., Crampton E. M., Frazer D. M., Anderson G. J. Subramaniam V. N. (2009) Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 50, 1992 2000.
168. Wang X. S., Lee S., Simmons Z., Boyer P., Scott K., Liu W. Connor J. (2004) Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences. J. Neurol. Sci. 227, 27 33.
169. Wang Q., Du F., Qian Z. M., Ge X. H., Zhu L., Yung W. H., Yang L. Ke Y. (2008) Lipopolysaccharide induces a significant increase in expression of iron regulatory hormone hepcidin in the cortex and substantia nigra in rat brain. Endocrinology 149, 3920 3925.
170. Whitlock E. P., Garlitz B. A., Harris E. L., Beil T. L. Smith P. R. (2006) Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 145, 209 223.
171. Wu L. J., Leenders A. G., Cooperman S. et al. (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res. 1001, 108 117.
172. Xu X., Pin S., Gathinji M., Fuchs R. Harris Z. L. (2004) Aceruloplasminemia: an inherited neurodegenerative disease with impairment of
173. Youdim M. B., Grunblatt E., Levites Y., Maor G. Mandel S. (2002) Early and late molecular events in neurodegeneration and neuroprotection in Parkinson's disease MPTP model as assessed by cDNA microarray; the role of iron. Neurotox. Res. 4, 679 689.
174. Zafeiriou D. I., Prengler M., Gombakis N. et al. (2004) Central nervous system abnormalities in asymptomatic young patients with Sbeta-thalassemia. Ann. Neurol. 55, 835 839.
175. Zecca L., Fariello R., Riederer P., Sulzer D., Gatti A. Tampellini D. (2002) The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson's disease. FEBS Lett. 510, 216 220.
176. Zechel S., Huber-Wittmer K. von Bohlen und Halbach O. (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J. Neurosci. Res. 84, 790 800.
177. Zhang A. S. Enns C. A. (2009) Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J. Biol. Chem. 284, 711 715.
178. Zhang Y., Tatsuno T., Carney J. M. Mattson M. P. (1993) Basic FGF, NGF, and IGFs protect hippocampal and cortical neurons against iron-induced degeneration. J. Cereb. Blood Flow Metab. 13, 378 388.
179. Zhao M., Antunes F., Eaton J. W. Brunk U. T. (2003) Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis. Eur. J. Biochem. 270, 3778 3786.
180. Zhou B., Westaway S. K., Levinson B., Johnson M. A., Gitschier J. Hayflick S. J. (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345 349.