Iron dysregulation and neurodegeneration: The molecular connection

Molecular Interventions

Volumn 6, Issue 2, 2006, Pages 89-97

  Lee, Donna W ^a   Andersen, Julie K ^a   Kaur, Deepinder ^a  

^a BUCK INSTITUTE FOR RESEARCH ON AGING   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CERULOPLASMIN; FERRITIN; FRATAXIN; GROWTH FACTOR; HEME OXYGENASE 1; HEREDITARY HEMOCHROMATOSIS PROTEIN; IRON; IRON REGULATORY FACTOR; METALOTHIONEIN; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; TRANSFERRIN RECEPTOR; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; BRAIN REGION; CATARACT; CENTRAL NERVOUS SYSTEM; FRIEDREICH ATAXIA; HEMOCHROMATOSIS; HUMAN; IRON METABOLISM; NERVE DEGENERATION; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PROTEIN DEFECT; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW;

ANIMALS; CATION TRANSPORT PROTEINS; CERULOPLASMIN; HEME OXYGENASE-1; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IRON; IRON METABOLISM DISORDERS; IRON-BINDING PROTEINS; IRON-REGULATORY PROTEINS; MEMBRANE PROTEINS; METALLOPROTEINS; MICE; MICE, TRANSGENIC; MODELS, BIOLOGICAL; MUTATION; NERVE DEGENERATION; NEURODEGENERATIVE DISEASES; PHOSPHOTRANSFERASES (ALCOHOL GROUP ACCEPTOR);

EID: 33645326193     PISSN: 15340384     EISSN: None     Source Type: Journal    
DOI: 10.1124/mi.6.2.6     Document Type: Review

References (65)

1. Cairo, G., and Pietrangelo, A. Iron regulatory proteins in pathobiology. Biochem. J. 352 (Pt 2), 241-250 (2000). Excellent review focusing on the functioning of iron regulatory proteins under various pathological conditions.
2. Papanikolaou, G. and Pantopoulos, K. Iron metabolism and toxicity. Toxicol. Appl. Pharmacol. 202, 199-211 (2005). Comprehensive review which provides background on the biology and toxicity of iron and the basic concepts of iron homeostasis at the cellular and systemic level.
3. Moos, T. and Morgan, E.H. The metabolism of neuronal iron and its pathogenic role in neurological disease: Review. Ann. N.Y. Acad. Sci. 1012, 14-26 (2004). An excellent, lucid review on iron metabolism of neurons in particular under normal and pathogenic conditions.
4. Ponka, P. Hereditary causes of disturbed iron homeostasis in the central nervous system. Ann. N.Y. Acad. Sci. 1012, 267-281 (2004). An excellent review providing an overview of iron metabolism and several hereditary iron-overloading conditions that are confined to the brain.
5. Bishop, G.M., Robinson, S.R., Liu, Q., Perry, G., Atwood, C.S., and Smith, M.A. Iron: A pathological mediator of Alzheimer disease? Dev. Neurosci. 24, 184-187 (2002).
6. Kaur, D. and Andersen, J. Does cellular iron dysregulation play a causative role in Parkinson's disease? Ageing Res. Rev. 3, 327-343 (2004).
7. Ke, Y. and Ming Qian, Z. Iron misregulation in the brain: A primary cause of neurodegenerative disorders. Lancet Neurol. 2, 246-253 (2003). A well written and illustrated review on genetic and non-genetic factors underlying iron-mediated neurodegeneration
8. Schneider, B.D. and Leibold, E.A. Regulation of mammalian iron homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 3, 267-273 (2000).
9. Meyron-Holtz, E.G., Ghosh, M.C., Iwai, K. et al. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 23, 386-395 (2004).
10. LaVaute, T., Smith, S., Cooperman, S. et al. 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 (2001). Groundbreaking paper describing iron dysregulation and age-related neurodegeneration associated with IRP2 deletion.
11. Smith, S.R., Cooperman, S., Lavaute, T. et al. Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies. Ann. N.Y. Acad. Sci. 1012, 65-83 (2004).
12. Vidal, R., Delisle, M.B., and Ghetti, B. Neurodegeneration caused by proteins with an aberrant carboxyl-terminus. J. Neuropathol. Exp. Neurol. 63, 787-800 (2004).
13. Ferreira, C., Bucchini, D., Martin, M.E., Levi, S., Arosio, P., Grandchamp, B., and Beaumont, C. Early embryonic lethality of H ferritin gene deletion in mice. J. Biol. Chem. 275, 3021-3024 (2000). A very important paper showing the indispensable nature of the ferroxidase function of H ferritin.
14. Cozzi, A., Corsi, B., Levi, S., Santambrogio, P., Biasiotto, G., and Arosio, P. Analysis of the biologic functions of H- and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: Evidence for a proliferative role of L-ferritin. Blood 103, 2377-2383 (2004).
15. Curtis, A.R., Fey, C., Morris, C.M. et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet. 28, 350-354 (2001). Original paper describing how defects in L Ferritin translate into neuroferritinopathy.
16. Vidal, R., Delisle, M.B., Rascol, O., and Ghetti, B. Hereditary ferritinopathy. J. Neurol. Sci. 207, 110-111 (2003).
17. Levi, S., Cozzi, A., and Arosio, P. Neuroferritinopathy: A neurodegenerative disorder associated with L-ferritin mutation. Best Pract. Res. Clin. Haematol. 18, 265-276 (2005).
18. Girelli, D., Bozzini, C., Zecchina, G. et al. Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia- cataract syndrome. Br. J. Haematol. 115, 334-340 (2001).
19. Xu, X., Pin, S., Gathinji, M., Fuchs, R., and Harris, Z.L. Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis. Ann. N.Y. Acad. Sci. 1012, 299-305 (2004). An excellent, concise overview of how iron is dysregulated in aceruloplasminemia.
20. Harris, Z.L., Durley, A.P., Man, T.K., and Gitlin, J.D. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl. Acad. Sci. U.S.A. 96, 10812-10817 (1999).
21. Hahn, P., Qian, Y., Dentchev, T., Chen, L., Beard, J., Harris, Z.L., and Dunaief, J.L. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc. Natl. Acad. Sci. U.S.A. 101, 13850-13855 (2004).
22. Klomp, L.W., Farhangrazi, Z.S., Dugan, L.L., and Gitlin, J.D. Ceruloplasmin gene expression in the murine central nervous system. J. Clin. Invest. 98, 207-215 (1996).
23. Jeong, S.Y. and David, S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J. Biol. Chem. 278, 27144-27148 (2003). This study provided evidence to show the interaction of Cp with IREG1 and essentiality of this interaction for astrocytic iron efflux.
24. Templeton, D.M. and Liu, Y. Genetic regulation of cell function in response to iron overload or chelation. Biochim. Biophys. Acta 1619, 113-124 (2003).
25. Fleming, M.D., Trenor, C.C., 3rd, Su, M.A., Foernzler, D., Beier, D.R., Dietrich, W.F., and Andrews, N.C. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16, 383-386 (1997).
26. Moos, T. and Morgan, E.H. The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J. Neurochem. 88, 233-245 (2004).
27. Huang, E., Ong, W.Y., Go, M.L., and Connor, J.R. Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury. Exp. Brain Res. 1-11 (2005).
28. Campuzano, V., Montermini, L., Molto, M.D. et al. Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423-1427 (1996).
29. Koutnikova, H., Campuzano, V., Foury, F., Dolle, P., Cazzalini, O., and Koenig, M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat. Genet. 16, 345-351 (1997).
30. Babcock, M., de Silva, D., Oaks, R., Davis-Kaplan, S., Jiralerspong, S., Montermini, L., Pandolfo, M., and Kaplan, J. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276, 1709-1712 (1997). One of the two seminal papers that provided evidence to link frataxin to the regulation of mitochondrial iron.
31. Park, S., Gakh, O., O'Neill, H.A., Mangravita, A., Nichol, H., Ferreira, G.C. and Isaya, G. Yeast frataxin sequentially chaperones and stores iron by coupling protein assembly with iron oxidation. J. Biol. Chem. 278, 31340-31351 (2003).
32. Gakh, O., Park, S., Liu, G., Macomber, L., Imlay, J.A., Ferreira, G.C., and Isaya, G. Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum. Mol. Genet. 15, 467-479 (2006). A breakthrough paper suggesting that the iron detoxification function of frataxin can contribute to antioxidant defenses and cell longevity.
33. Zhou, B., Westaway, S.K., Levinson, B., Johnson, M.A., Gitschier, J., and Hayflick, S.J. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345-349 (2001). Pioneering report identifying a genetic basis for NBIA (Neurodegeneration with Brain Iron Accumulation) in the form of PANK2 mutation.
34. Gordon, N. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). Eur. J. Paediatr. Neurol. 6, 243-247 (2002).
35. Hayflick, S.J. Unraveling the Hallervorden-Spatz syndrome: Pantothenate kinase-associated neurodegeneration is the name. Curr. Opin. Pediatr. 15, 572-577 (2003).
36. Leonardi, R., Zhang, Y.M., Rock, C.O., and Jackowski, S. Coenzyme A: Back in action. Prog. Lipid Res. 44, 125-153 (2005).
37. Johnson, M.A., Kuo, Y.M., Westaway, S.K., Parker, S.M., Ching, K.H., Gitschier, J., and Hayflick, S.J. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann. N.Y. Acad. Sci. 1012, 282-298 (2004).
38. Rouault, T.A. Iron on the brain. Nat. Genet. 28, 299-300 (2001).
39. Perry, T.L., Norman, M.G., Yong, V.W., Whiting, S., Crichton, J.U., Hansen, S,. and Kish, S.J. Hallervorden-Spatz disease: Cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus. Ann. Neurol. 18, 482-489 (1985).
40. Feder, J.N., Penny, D.M., Irrinki, A. Et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc. Natl. Acad. Sci. U.S.A. 95, 1472-1427 (1998). Key report showing the mechanism of iron dysregulation in hereditary haemochromatosis.
41. Feder, J.N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D.A., and Basava, A. The discovery of the new haemochromatosis gene. 1996. J. Hepatol. 38, 704-709 (2003).
42. Feder, J.N., Gnirke, A., Thomas, W. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399-408 (1996). First report identifying the genetic basis of hereditary haemochromatosis.
43. Merryweather-Clarke, A.T., Pointon, J.J., Shearman, J.D., and Robson, K.J. Global prevalence of putative haemochromatosis mutations. J. Med. Genet. 34, 275-278 (1997).
44. Connor, J.R. and Benkovic, S.A. Iron regulation in the brain: Histochemical, biochemical, and molecular considerations. Ann. Neurol. 32 Suppl, S51-S61 (1992).
45. Bartzokis, G., Sultzer, D., Cummings, J., Holt, L.E., Hance, D.B., Henderson, V.W. and Mintz, J. In vivo evaluation of brain iron in Alzheimer disease using magnetic resonance imaging. Arch. Gen. Psychiatry 57, 47-53 (2000).
46. Connor, J.R., Milward, E.A., Moalem, S., Sampietro, M., Boyer, P., Percy, M.E., Vergani, C., Scott, R.J. and Chorney, M. Is hemochromatosis a risk factor for Alzheimer's disease? J. Alzheimers Dis. 3, 471-477 (2001).
47. Markesbery, W.R. Oxidative stress hypothesis in Alzheimer's disease. Free Radic. Biol. Med. 23, 134-147 (1997).
48. Buchanan, D.D., Silburn, P.A., Chalk, J.B., Le Couteur, D.G., and Mellick, G.D. The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients. Neurosci. Lett. 327, 91-94 (2002).
49. Connor, J.R., Snyder, B.S., Arosio, P., Loeffler, D.A., and LeWitt, P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J. Neurochem. 65, 717-724 (1995).
50. Dekker, M.C., Giesbergen, P.C., Njajou, O.T., van Swieten, J.C., Hofman, A., Breteler, M.M., and van Duijn, C.M. Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism. Neurosci. Lett. 348, 117-119 (2003).
51. Bastin, J.M., Jones, M., O'Callaghan, C.A., Schimanski, L., Mason, D.Y., and Townsend, A.R. Kupffer cell staining by an HFE-specific monoclonal antibody: Implications for hereditary haemochromatosis. Br. J. Haematol. 103, 931-941 (1998).
52. Grammas, P. A damaged microcirculation contributes to neuronal cell death in Alzheimer's disease. Neurobiol. Aging 21, 199-205 (2000).
53. Moalem, S., Percy, M.E., Andrews, D.F., Kruck, T.P., Wong, S., Dalton, A.J., Mehta, P., Fedor, B., and Warren, A.C. Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am. J. Med. Genet. 93, 58-66 (2000).
54. Sampietro, M., Caputo, L., Casatta, A., Meregalli, M., Pellagatti, A., Tagliabue, J., Annoni, G., and Vergani, C. The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease. Neurobiol. Aging 22, 563-568 (2001).
55. Pulliam, J.F., Jennings, C.D., Kryscio, R.J., Davis, D.G., Wilson, D., Montine, T.J., Schmitt, F.A., and Markesbery, W.R. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer disease and correlation with APOE. Am. J. Med. Genet. B Neuropsychiatr. Genet. 119, 48-53 (2003).
56. Ryter, S.W. and Tyrrell, R.M. The heme synthesis and degradation pathways: Role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic. Biol. Med. 28, 289-309 (2000). An excellent hypothesis paper that presents the fate of iron through the heme synthesis and degradation pathways as well as the role that heme oxgenases play in promoting pro- and/or anti-oxidant cellular environments.
57. Ferris, C.D., Jaffrey, S.R., Sawa, A. et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat. Cell Biol. 1, 152-157 (1999). One of the earlier papers to link iron from a HO-mediated reaction with cytoprotection.
58. Schipper, H.M., Bernier, L., Mehindate, K., and Frankel, D. Mitochondrial iron sequestration in dopamine-challenged astroglia: Role of heme oxygenase-1 and the permeability transition pore. J. Neurochem. 72, 1802-1811 (1999). A comprehensive review of neurodegenerative disorders associated with iron dysregulation and introduction of the "free radical-mitochondrial" theory of brain aging.
59. Schipper, H.M. Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res. Rev. 3, 265-301 (2004).
60. Aschner, M. The functional significance of brain metallothioneins. FASEB J. 10, 1129-1136 (1996).
61. Uchida, Y., Takio, K., Titani, K., Ihara, Y., and Tomonaga, M. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Neuron 7, 337-347 (1991).
62. Miyazaki, I., Asanuma, M., Higashi, Y., Sogawa, C.A., Tanaka, K., and Ogawa, N. Age-related changes in expression of metallothionein-III in rat brain. Neurosci. Res. 43, 323-333 (2002).
63. Ebadi, M., Brown-Borg, H., El Refaey, H., Singh, B.B., Garrett, S., Shavali, S., and Sharma, S.K. Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Brain Res. Mol. Brain Res. 134, 67-75 (2005). An extensive review of the literature that implicated the neuroprotective effects of MTs in degenerating DAergic neurons in in vivo models.
64. Doraiswamy, P.M. and Finefrock, A.E. Metals in our minds: Therapeutic implications for neurodegenerative disorders. Lancet Neurol. 3, 431-434 (2004).
65. Youdim, M.B., Stephenson, G., and 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. N.Y. Acad. Sci. 1012, 306-325 (2004).