Iron, brain ageing and neurodegenerative disorders

Nature Reviews Neuroscience

Volumn 5, Issue 11, 2004, Pages 863-873

  Zecca, Luigi ^a   Youdim, Moussa B H ^b   Riederer, Peter ^c   Connor, James R ^d   Crichton, Robert R ^e  

^a CNR   (Italy)

^b TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

^c UNIVERSITY OF WÜRZBURG   (Germany)

^d PENN STATE MILTON S HERSHEY MEDICAL CENTER   (United States)

^e UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; AMYLOID PRECURSOR PROTEIN; APOTRANSFERRIN; CERULOPLASMIN; CHELATING AGENT; CLIOQUINOL; CURCUMIN; CYTOCHROME C; CYTOCHROME REDUCTASE; DEFEROXAMINE MESYLATE; DOPAMINE; EPIGALLOCATECHIN GALLATE; FERRITIN; FRATAXIN; HEME OXYGENASE 1; HEMOSIDERIN; HEPCIDIN; IDEBENONE; IRON; LACTOFERRIN; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; NEUROMELANIN; PENICILLAMINE; PROTEIN; RASAGILINE; TRANSFERRIN; TRANSFERRIN RECEPTOR; TYROSINE 3 MONOOXYGENASE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VK 28;

AGING; ALZHEIMER DISEASE; BRAIN; CARDIOMYOPATHY; DEGENERATIVE DISEASE; DISEASE ASSOCIATION; DOPAMINERGIC NERVE CELL; FRIEDREICH ATAXIA; GENE MUTATION; GLOBUS PALLIDUS; HALLERVORDEN SPATZ DISEASE; HUMAN; IRON DEFICIENCY; IRON METABOLISM; IRON OVERLOAD; LOCUS CERULEUS; NEUROTOXICITY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OXIDATIVE STRESS; PARKINSON DISEASE; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PUTAMEN; RESTLESS LEGS SYNDROME; REVIEW; SUBSTANTIA NIGRA; WILSON DISEASE;

AGING; BRAIN; HUMANS; IRON; NEURODEGENERATIVE DISEASES;

ATAXIA;

EID: 8344265251     PISSN: 1471003X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrn1537     Document Type: Review

References (137)

1. Crichton, R. R. Inorganic Biochemistry of Iron Metabolism: From Molecular Mechanisms to Clinical Consequences (John Wiley & Sons, Chichester, 2001). A comprehensive overview of iron biochemistry, from molecules to medicine.
2. Pigeon, C. et al. 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 (2001).
3. Nicolas, G. et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl Acad. Sci. USA 98, 8780-8785 (2001).
4. Papanikolaou, G. et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nature Genet. 36, 77-82 (2004).
5. Andrews, N. C. Iron homeostasis: insights from genetics and animal models. Nature Rev. Genet. 1, 208-217 (2000).
6. Andrews, N. C. The iron transporter DMT1. Int. J. Biochem. Cell. Biol. 31, 991-994 (1999).
7. Kawabata, H. et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J. Biol. Chem. 274, 20826-20832 (1999).
8. Eisenstein, R. S. Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu. Rev. Nutr. 20, 627-662 (2000). A recent review of the translational control of iron homeostasis.
9. Aisen, P., Enns, C. & Wessling-Resnick, M. Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell. Biol. 33, 940-959 (2001). A recent review of eukaryotic iron metabolism.
10. Burdo, J. R. & Connor, J. R. Brain iron uptake and homeostatic mechanisms: an overview. BioMetals 16, 63-75 (2003). This review provides an up-to-date assessment of the knowledge of iron transport into the brain. The article identifies the flaws in the current thinking about mechanisms of transport and reveals that little is known about the regulation of these mechanisms. Moreover, the article introduces new research directions and concepts.
11. Koeppen, A. H. The history of iron in the brain. J. Neurol. Sci. 134 (Suppl.), 1-9 (1995).
12. Connor, J. R. & Menzies, S. L. Cellular management of iron in the brain. J. Neurol. Sci. 134 (Suppl.), 33-44 (1999). This article establishes that there are differences in cellular iron usage and regulation among the specific cell types in the brain by demonstrating the differences in cell-specific ratios between H- and L-ferritin subunits.
13. Connor, J. R., Boeshore, K. L. & Benkovic, S. A. Isoforms of ferritin have a specific cellular distribution in the brain. J. Neurosci. Res. 37, 461-465 (1994).
14. Moos, T. & Morgan, E. H. The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann. NY Acad. Sci. 1, 1012-1014 (2004).
15. Zecca, L. et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigraduring aging. Proc. Natl Acad. Sci. USA 101, 9843-9848 (2004). This is the first study on iron, neuromelanin and ferritin in the locus coeruleus that provides an accurate comparison with iron in the substantia nigra. The age trend and cellular distribution in the locus coeruelus and substantia nigra is reported.
16. Zecca, L. et al. Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience 73, 407-415 (1996). This study shows that neuromelanin chelates iron-forming stable complexes in the substantia nigra and other brain regions.
17. Sulzer, D. et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesides. Proc. Natl Acad. Sci. USA 97, 11869-11874 (2000).
18. Zecca, L., Zucca, F. A., Wilms, H. & Sulzer, D. Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics. Trends Neurosci. 26, 578-580 (2003).
19. Wakamatsu, K., Fujikawa, K., Zucca, F. A., Zecca, L. & Ito, S. The structure of neuromelanin as studied by chemical degradative methods. J. Neurochem. 86, 1015-1023 (2003).
20. Bartlett, W. P., Li, X. S. & Connor, J. R. Expression of the transferrin mRNA in jimpy mice. J. Neurochem. 57, 318-322 (1991).
21. Connor, J. R. et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 62, 1563-1567 (2004).
22. de Arriba Zerpa, G. A. et al. Alternative splicing prevents transferrin differentiation of a human oligodendrocyte cell line. J. Neurosci. Res. 61, 388-395 (2000).
23. Hulet, S.W., Powers, S. & Connor, J. R. Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J. Neurol. Sci. 165, 48-55 (1999).
24. Hallgren, B. & Sourander, P. The effect of aging on the non-haemin iron in the human brain. J. Neurochem. 3, 41-51 (1958).
25. Connor, J. R., Snyder, B. S., Arosio, P., Loeffler, D. A. & LeWitt, P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian and Alzheimer Disease brains. J. Neurochem. 65, 717-724 (1995).
26. Zecca, L. et al. Iron, neuromelanin and ferritin in substantia nigra of normal subjects at different ages. Consequences for iron storage and neurodegenerative disorders. J. Neurochem. 76, 1766-1773 (2001).
27. Hirose, W., Ikematsu, K. & Tsuda, R. Age-associated increase in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Leg. Med. 5 (Suppl. 1), S360-S366 (2003).
28. Connor, J. R., Menzies, S. L., St. Martin, S. M. & Mufson, E. J. Cellular distribution of transferrin, ferritin and iron in normal and aged human brains. J. Neurosci. Res. 27, 595-611 (1990).
29. Bartzokis, G. et al. MR evaluation of brain iron in young adults and older normal males. Magn. Reson. Imaging 15, 29-35 (1997). References 29 and 74 establish the strength of MRI in examining brain iron distribution and changes in the brain with ageing. In particular, they establish a potential new tool in the evaluation of brain iron changes in normal and disease states, and expand on an important but under-appreciated concept that cognitive decline with ageing could be initiated in the white matter.
30. Martin, W. R., Ye, F. Q. & Allen, P. S. Increasing striatal iron content associated with normal aging. Mov. Disord. 13, 281-286 (1998).
31. Ogg, R. J., Langston, J. W., Haacke, E. M., Steen, R. G. & Taylor, J. S. The correlation between phase shifts in gradient-echo MR images and regional brain iron concentration. Magn. Reson. Imaging 17, 1141-1148 (1999).
32. Brun, A. & Englund, E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann. Neurol. 19, 253-262 (1986).
33. Snowdon, D. A. Nun Study. Healthy aging and dementia: findings from the Nun Study. Ann. Intern. Med. 139, 450-454 (2003).
34. Faucheux, B. A., Bonnet, A. M., Agid, Y. & Hirsch, E. C. Blood vessels change in the mesencephalon of patients with Parkinson's disease. Lancet 353, 981-982 (1999). This paper reports that increased iron concentration in the mesencephalon of patients with PD could be related to altered vascularization.
35. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Rev. Neurosci. 5, 347-360 (2004).
36. Jellinger, K., Paulus, W., Grundke-Iqbal, I., Riederer, P. & Youdim, M. B. Brain iron and ferritin in Parkinson's and Alzheimer's disease. J. Neural. Transm. Park. Dis. Dement. Sect. 2, 327-340 (1990).
37. Riederer, P. et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52, 516-520 (1989). This paper describes the first systematic determination of iron concentrations, GSH, vitamin C and ferritin in the substantia nigra in individuals with PD.
38. Dexter, D. T. et al. Increased nigral iron content in post-mortem parkinsonian brain. Lancet 341, 1219-1220 (1987).
39. Hirsch, E. C., Brandel, J.-R, Galle, P., Javoy-Agid, F. & Agid, Y. Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis. J. Neurochem. 56, 446-451 (1991).
40. Götz, M. E., Double, K., Gerlach, M., Youdim, M. B. & Riederer, P. The relevance of iron in the pathogenesis of Parkinson's disease. Ann. NY Acad. Sci. 1012, 193-208 (2004).
41. Uitti, R. J. et al. Regional metal concentrations in Parkinson's disease, other chronic neurological diseases, and control brains. Can. J. Neurol. Sci. 16, 310-314 (1989).
42. Galazka-Friedman, J. et al. Iron in parkinsonian and control substantia nigra: a Mossbauer spectroscopy study. Mov. Disord. 11, 8-16 (1996).
43. Griffiths, P. D., Dobson, B. R., Jones, G. R. & Clarke, D. T. Iron in the basal ganglia in Parkinson's disease: an in vitro study using extended X-ray absorption fine strucutre and cryo-electron microscopy. Brain 122, 667-673 (1999).
44. Dexter, D. T. et al. 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, 1953-1975 (1991).
45. Gerlach, M., Ben-Shachar, D., Riederer, P. & Youdim, M. B. Altered brain metabolism of iron as a cause of neurodegenerative diseases? J. Neurochem. 63, 793-807 (1994).
46. Owen, A. D., Schapira, A. H. V., Jenner, P. & Marsden, C. D. Indices of oxidative stress in Parkinson's disease, Alzheimer's disease, and dementia with Lewy bodies. J. Neural. Transm. 51 (Suppl.), 167-173 (1997).
47. Jellinger, K. et al. Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J. Neurochem. 59, 1168-1171 (1992).
48. Ben-Shachar, D., Eshel, G., Finberg, J. P. & Youdim, M. B. The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J. Neurochem. 56, 1441-1444 (1991). This paper describes the first use of an iron chelator, desferal, as a neuroprotective drug in a model of PD.
49. Double, K. L. et al. Iron-binding characteristics of neuromelanin of the human substantia nigra. Biochem. Pharmacol. 66, 489-494 (2003).
50. Good, P., Olanow, C. W. & Perl, D. P. Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminium in Parkinson's disease: a LAMMA study. Brain Res. 593, 343-346 (1992).
51. Wilms, H. et al. Activation of microglia by human neuromelanin is NF-κB dependent and involves p38 mitogen-activated protein kinase: implications for Parkinson's disease. FASEB J. 17, 500-502 (2003). This study demonstrates that the neuromelanin-iron complexes that occur extraneuronally in PD can activate microglia, thereby aggravating neurodegeneration in this disease.
52. Langston, J. W. et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyt-4-phenyl-1,2,3,6- tetrahydropyridine exposure. Ann. Neurol. 46, 598-605 (1999).
53. Gorell, J. M. et al. Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease. Neurology 45, 1138-1143 (1995). This study uses MRI to show iron accumulation in the substantia nigra of patients with PD.
54. Ryvlin, P. et al. Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson's disease. Arch. Neurol. 52, 583-588 (1995).
55. Berg, D. et al. Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch. Neurol. 59, 999-1005 (2002).
56. Faucheux, B. A. et al. Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinsons disease. J. Neurochem. 86, 1142-1148 (2003).
57. Schipper, H. M., Liberman, A. & Stopa, E. G. Neural heme oxygenase-1 expression in idiopathio Parkinsons disease. Exp. Neurol. 150, 60-68 (1998).
58. Qian, Z. M. & Wang, Q. Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res. Brain Res. Rev. 27, 257-267 (1998).
59. 125I]-transferrin binding sites on perikarya of melanized neurons of the substantia nigra is decreased in Parkinson's disease. Brain Res. 749, 170-174 (1997).
60. Faucheux, B. A. et al. Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. Proc. Natl Acad Sci. USA 92, 9603-9607 (1995).
61. Leveugle, B. et al. Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinsons disease cases. Acta Neuropathol. (Bert.) 91, 566-572 (1996).
62. Faucheux, B. A. et al. 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 (2002).
63. Borie, C. et al. French Parkinsons disease genetic study group. Association study between iron-related genes polymorphisms and Parkinsons disease. J. Neurol. 249, 801-804 (2002).
64. Leenders, K. L. et al. Verapamil uptake in mesecephalon of Parkinson disease. Ann. Neurol. (in the press).
65. Vila, M. et al. α-synudein up-regulation in substantia nigra dopamrergic neurons following administration of the parkinsonian toxin MPTP. J. Neurochem. 74, 721-729 (2000).
66. Mandel, S., Maor, G. & Youdim, M. B. H. Iron and α synuclein in the substantia nigra of MPTP treated mice; effect of neuroproteclive drugs R-apomorphine and green tea polyphenol epipgallocatechin-3-gallate. J. Mol. Neurosci. (in the press).
67. Ostrerova-Golts, N. et al. The A53T α-synudein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048-6054 (2000). This study indicates that α-synuclein can interact with iron to induce the formation of intracellular aggregates, and reports on the consequent effect on neuronal death in PD.
68. Uversky, V. N., Li, J. & Fink, A. L. Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein. A possible molecular link between Parkinson's disease and heavy metal exposure. J. Biol. Chem. 276, 44284-44296 (2001).
69. Münch, G. et al. Crosslinking of α-synuclein by advanced glycation endproducts - an early pathophysiological step in Lewy body formation? J. Chem. Neuroanat. 20, 253-257 (2000).
70. Hashimoto, M., Takeda, A., Hsu, L. J., Takenouchi, T. & Masliah, E. Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease. J. Biol. Chem. 274, 28849-28852 (1999).
71. Levine, S., Connor, J. & Schipper, H. Redox-active metals in neurological disorders. Ann. NY Acad. Sci. 1012, (2004).
72. Connor, J. R., Snyder, B. S., Beard, J. L., Fine, R. E. & Mufson, E. J. Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimers disease. J. Neurosci. Res. 31, 327-335 (1992).
73. Thompson, K. et al. 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 (2003).
74. Bartzokis, G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimers disease. Neurobiol. Aging 25, 5-18 (2004).
75. Rogers, J. T. et al. An iron-responsive element type II in the 5́-untranslated region of the Alzheimer's amyloid precursor protein transcript. J. Biol. Chem. 277, 45518-45528 (2002). This study raises the possibility that APP production and synthesis could be influenced by cellular iron status through an IRE on the APP mRNA. This mechanism has the potential to integrate a number of different aspects of iron changes, amyloid deposition and oxidative stress.
76. Bodovitz, S., Falduto, M. T., Frail, D. E. & Klein, W. L. Iron levels modulate α-secretase cleavage of amyloid precursor protein. J. Neurochem. 64, 307-315 (1995).
77. Huang, X. et al. Alzheimer's disease, β-amyloid protein and zinc. J. Nutr. 130, 1488S-1492S (2000).
78. Rottkamp, C. A. et al. Redox-active iron mediates amytoid-β toxicity. Free Radic. Biol. Med. 30, 447-450 (2001).
79. Mantyn, P. et al. Aluminum, iron and zinc ions promote aggregation of physiological concentrations of β-amyloid peptide. J. Neurochem. 61, 1171-1174 (1993).
80. Perry, G. et al. The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications. CNS Drugs 16, 339-352 (2002),
81. Bush, A. I. Metal complexing agents as therapies for Alzheimer's disease. Neurobiol. Aging 23, 1031-1038 (2002).
82. Ritchie, C. W. et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial Arch. Neurol. 60, 1686-1691 (2003).
83. Ben Shachar, D., Kahana, N., Kampel, V., Warshawsky, A. & Youdim, M. B. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lesion in rats. Neuropharmacology 46, 254-263 (2004).
84. Youdim, M. B. H., Fridkin, M. & Zheng, H. Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson's disease and other neurodegenerative diseases. J. Neural. Transm. 1435-1463 (Online) (2004). This paper describes the development of the first brain-permeable bifunctional iron chelator-MAO inhibitor, which Is derived from the prototype brain-permeable neuroprotective iron chelator VK-28.
85. Connor, J. R. et al. Is hemochromatosis a risk factor for Alzheimer's disease? J. Afenamers Dis. 3, 471-477 (2001).
86. Lee, S. & Connor, J. R. Regulation of Hfe by stress factors in BV-2 cells. Neurobiol. Aging (in the press).
87. Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13, 399-408 (1996).
88. Moalem, S. et al. Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am. J. Med. Genet. 93, 58-66 (2000).
89. Braak, H., Braak, E. & Bohl, J. Staging of Alzheimer-related cortical destruction. Eur. Neurol. 33, 403-408 (1993).
90. Pulliam, J. F. et al. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with APOE. Am. J. Med. Genet. 1198, 48-53 (2003).
91. Namekata, K. et al. Association of transferrin C2 allele with late-onset Alzheimer's disease. Hum. Genet 101, 126-129 (1997).
92. Van Landeghem, Q., Sikstrom, C., Beckman, L, Adolfsson, R. & Beckman, R. Transferrin C2, metal binding and Alzheimer's Disease. Neuroreport 9, 177-179 (1998).
93. Zambenedetti, P., De Bellis, G., Biunno, I., Musicco, M. & Zatta, R Transferrin C2 variant does confer a risk for Alzheimer's disease. J. Alzheimers Dis. 5, 423-427 (2003).
94. Hussain, R. I., Ballard, C. G., Edwardson, J. A. & Morris, C. M. Transferrin gene polymorphism in Alzheimer's disease and dementia with Lewy bodies in humans. Neurosci. Lett. 317, 13-16 (2002).
95. Robson, K. J. et al. Synergy between the C2 allele of transferrin and the C282Y allele of the haemoehromatosis gene (Hfe) as risk factors for developing Alzheimer's Disease. J. Med. Genet. 41, 261-265 (2004).
96. Ke, Y. & Ming Qian, Z. Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol. 2, 246-253 (2003). An overview of the role of misregulation of iron metabolism in neurodegeneration.
97. Nittis, T. & Gitlin, J. D. The copper-iron connection: hereditary aceruloplasminemia. Semin. Hematol. 39, 282-289 (2002).
98. Yoshida, K. et al. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nature Genet. 9, 267-272 (1995).
99. Harris, Z. L. et al. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc. Natl Acad. Sci. USA 92, 2539-2543 (1995). The copper-iron relationship explained.
100. Miyajama, H. et al. The use of deferrioxamine in the treatment of aceruloplasminemia. Ann. Neurol. 41, 404-407 (1997).
101. Harris, Z. L. et al. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl Acad. Sci. USA 96, 10812-10817 (1999).
102. Patel, P. I. & Isaya, G. Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am. J. Hum. Genet 69, 15-24 (2001).
103. Zoghbi, H. Y. & Orr, H. T. Glutamine repeats and neurodegeneration, Ann. Rev. Neurosci. 23, 217-247 (2000). This review discusses the consequences of too many glutamine repeats.
104. Gordon, N. Friedreich's ataxia and iron metabolism. Brain Dev. 22, 465-468 (2000).
105. Muhlenhoff, U., Richhardt, N., Ristow, M., Kispal, G. & Lill, R. The yeast frataxin homolog Yfh 1p plays a specific role in the maturation of cellular Fe/S proteins. Hum. Mol. Genet 11, 2025-2036 (2002).
106. Cooper, J. M. & Schapira, A. H. Friedreich's ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy. Biofactors 18, 163-171 (2003). A timely review of Friedreich's ataxia and antioxidant therapy.
107. Curtis, A. R. et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nature Genet 28, 350-354 (2001).
108. Crompton, D. E. et al. Neuroferritinopathy: a window on the role of iron in neurodegeneration. Blood Cells Mol. Dis. 29, 522-531 (2002).
109. Vidal, R. et al. Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J. Neuropathol. Exp. Neurol. 63, 363-380 (2004).
110. Zhou, B. et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nature Genet 4, 345-349 (2001).
111. Hayflick, S. J. Unravelling the Hallervorden-Spatz syndrome: pantothenate kinase-associated neurodegeneration is the name. Curr. Opin. Pediatr. 15, 572-577 (2003).
112. Beard, J. L. & Connor, J. R. Iron Status and Neural Functioning. Annu. Rev. Nutr. 23, 41-58 (2003).
113. Earley, C. J. Clinical practice. Restless legs syndrome. N. Engl. J. Med. 348, 2103-2109 (2003).
114. Youdim, M. B., Ben-Shachar, D. & Riederer, P. The possible role of iron in the etiopathology of Parkinson's disease. Mov. Disord. 8, 1-12 (1993).
115. Ponka, P. Hereditary causes of disturbed iron homeostasis in the centra nervous system. Ann. NY Acad. Sci. 1012, 267-281 (2004).
116. Youdim, M. B. H. & Riederer, P. in Encyclopedia of Neuroscience (Elsevier, Amsterdam, 2004). A review about brain iron in normal and pathological conditions.
117. Barnham, K. J., Masters, C. L. & Bush, A. I. Neurodegenerative diseases and oxidative stress. Nature Rev. Drug Discov. 3, 205-214 (2004).
118. LaVaute, T. et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nature Genet. 27, 209-214 (2001).
119. Youdim, M. B. H., Stephenson, G. & Ben Shachar, D. Ironing iron out in Parkinson's disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28. Ann. NY Acad. Sci. 1012, 306-325 (2004).
120. Wang, X. S., Ong, W. Y. & Connor, J. R. Quinacrine attenuates increases in divalent metal fransporter-1 and iron levels in the rat hippocampus, after kainate-induced neuronal injury. Neuroscience 120, 21-29 (2003).
121. Cohen, G, Oxidative stress, mitochondrial respiration, and Parkinson's disease. Ann. NY Acad. Sci. 899, 112-120 (2000).
122. Jenner, P. & Olanow, C. W. Understanding cell death in Parkinson's disease. Ann. Neurol. 44 (3 Suppl. 1), S72-S84 (1998).
123. Mandel, S., Weinreb, O. & Youdim, M. B. Using cDNA microarray to assess Parkinson's disease models and the effects of neuroprotective drugs. Trends Pharmacol. Sci. 24, 184-191 (2003).
124. Temlett, J. A., Landsberg, J. P., Watt, F. & Grime, G. W. Increased iron in the substantia nigra compacta of the MPTP-lesioned hemiparkinsonian African green monkey: evidence from proton microprobe elemental microanalysis. J. Neurochem. 62, 134-146 (1994).
125. Oestreicher, E. et al. Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: a histochemical and neurochemical study. Brain Res. 660, 8-18 (1994).
126. Shoham, S. & Youdim, M. B. Nutritional iron deprivation attenuates kainate-induced neurotoxicity in rats: implications for involvement of iron in neurodegeneration. Ann. NY Acad. Sci. 1012, 94-114 (2004).
127. Bharath, S., Hsu, M., Kaur, D., Rajagopalan, S. & Andersen, J. K. Glutathione, iron and Parkinson's disease. Biochem. Pharmacol. 64, 1037-1048 (2002).
128. Kaur, D. et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinsons disease. Neuron 27, 899-909 (2003). This study shows that lowering the concentration of free iron in the mouse brain reduces the neurotoxic effect of MPTP.
129. Moussaoui, S. et al. The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson's disease. Exp. Neurol. 166, 235-245 (2000).
130. Moosmann, B. & Behl, C. Antioxidants as treatment for neurodegenerative disorders. Expert Opin. Investig. Drugs. 11, 1407-1435 (2002).
131. Mandel, S., Weinreb, O., Amit, T. & Youdim, M. B. Cell signaling pathways in the neuroprotective actions of the green tea potyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J. Neurochem. 88, 1555-1569 (2004).
132. Rogers, J. T. & Lahiri, D. K. Metal and inflammatory targets for Alzheimer's disease. Curr. Drug Targets 5, 535-551 (2004).
133. Youdim, M. B. H. & Buccafesco, J. Multi-functional drugs for various CNS targets in the treatments of neurodegenerative diseases. Trends Pharmacol. Sci. (in the press).
134. Youdim, M. B. H. Rasagiline: an anti-Parkinson drug with neuroprotective activity. Expert Rev. Neurotherapeutics 3, 737-749 (2003).
135. Dexter, D. T., Ward, R. J., Rorence, A., Jenner, P. &. Crichton, R. R. Effects of desferrithiocin and its derivatives on peripheral iron and striatal dopamine and 5-hydroxytryptamine metabolism in the ferrocene-loaded rat. Biochem. Pharmacol. 58, 151-155 (1999).
136. Baum, L. & Ng, A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J. Alzheimers Dis. 6, 367-377 (2004).
137. 52Fe-citrate PET study. J. Nucl. Med. 41, 781-787 (2000).