Brain Iron Metabolism Dysfunction in Parkinson’s Disease

Molecular Neurobiology

Volumn 54, Issue 4, 2017, Pages 3078-3101

  Jiang, Hong ^a   Wang, Jun ^a   Rogers, Jack ^b   Xie, Junxia ^a  

^a QINGDAO UNIVERSITY MEDICAL COLLEGE   (China)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Brain iron metabolism; Iron chelation; Iron regulatory protein; Iron transporters; Parkinson s disease

Indexed keywords

ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; ALPHA SYNUCLEIN; CURCUMIN; DEFERIPRONE; EPIGALLOCATECHIN GALLATE; GINKGETIN; GINSENOSIDE; HERBACEOUS AGENT; IRON; IRON BINDING PROTEIN; IRON CHELATING AGENT; M 30; MEMBRANE PROTEIN; MYRICETIN; PROTEASOME; UBIQUITIN; UNCLASSIFIED DRUG; VAR 10303; VK 28; VOLTAGE GATED CALCIUM CHANNEL;

ALPHA SYNUCLEIN GENE; APOPTOSIS; BRAIN METABOLISM; CELL DEATH; CELL TRANSPORT; CURCUMA LONGA; DJ 1 GENE; DOPAMINERGIC NERVE CELL; GENE; GENE MUTATION; GINKGO BILOBA; HOMEOSTASIS AND REGULATION; HUMAN; ION TRANSPORT; IRON CHELATION; IRON KINETICS; IRON METABOLISM; IRON METABOLISM DISORDER; IRON STORAGE; IRON TRANSPORT; LRRK2 GENE; LYSOSOME; MITOCHONDRION; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; P53 GENE; PARKIN GENE; PARKINSON DISEASE; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PINK1 GENE; REVIEW; RHIZOME; SUBSTANTIA NIGRA; TUMOR SUPPRESSOR GENE; ANIMAL; BIOLOGICAL MODEL; BRAIN; HOMEOSTASIS; METABOLISM;

ANIMALS; BRAIN; HOMEOSTASIS; HUMANS; IRON; MITOCHONDRIA; MODELS, BIOLOGICAL; PARKINSON DISEASE;

EID: 84962197452     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-016-9879-1     Document Type: Review

References (278)

1. Schweitzer KJ, Brussel T, Leitner P, Kruger R, Bauer P, Woitalla D, Tomiuk J, Gasser T, Berg D (2007) Transcranial ultrasound in different monogenetic subtypes of Parkinson’s disease. J Neurol 254(5):613–616. doi:10.1007/s00415-006-0369-7
2. Hagenah JM, Konig IR, Becker B, Hilker R, Kasten M, Hedrich K, Pramstaller PP, Klein C, Seidel G (2007) Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles. J Neurol 254(10):1407–1413. doi:10.1007/s00415-007-0567-y
3. Hagenah JM, Becker B, Bruggemann N, Djarmati A, Lohmann K, Sprenger A, Klein C, Seidel G (2008) Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations. J Neurol Neurosurg Psychiatry 79(9):1071–1074. doi:10.1136/jnnp.2007.142174
4. Bruggemann N, Hagenah J, Stanley K, Klein C, Wang C, Raymond D, Ozelius L, Bressman S, Saunders-Pullman R (2011) Substantia nigra hyperechogenicity with LRRK2 G2019S mutations. Mov Disord 26(5):885–888. doi:10.1002/mds.23644
5. Xie W, Li X, Li C, Zhu W, Jankovic J, Le W (2010) Proteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease. J Neurochem 115(1):188–199. doi:10.1111/j.1471-4159.2010.06914.x
6. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52(6):1830–1836
7. Bastian TW, Prohaska JR, Georgieff MK, Anderson GW (2010) Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology 151(8):4055–4065. doi:10.1210/en.2010-0252
8. Ke Y, Ming Qian Z (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2(4):246–253
9. Kaur D, Andersen J (2004) Does cellular iron dysregulation play a causative role in Parkinson’s disease? Ageing Res Rev 3(3):327–343. doi:10.1016/j.arr.2004.01.003
10. Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68(21):1820–1825. doi:10.1212/01.wnl.0000262033.01945.9a
11. Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res. doi: 10.1038/cr.2010.20
12. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–1060. doi:10.1016/S1474-4422(14)70117-6
13. Ayton S, Lei P (2014) Nigral iron elevation is an invariable feature of Parkinson’s disease and is a sufficient cause of neurodegeneration. Biomed Res Int 2014:581256. doi:10.1155/2014/581256
14. Knutson M, Menzies S, Connor J, Wessling-Resnick M (2004) Developmental, regional, and cellular expression of SFT/UbcH5A and DMT1 mRNA in brain. J Neurosci Res 76(5):633–641. doi:10.1002/jnr.20113
15. McCarthy RC, Kosman DJ (2012) Mechanistic analysis of iron accumulation by endothelial cells of the BBB. Biometals 25(4):665–675. doi:10.1007/s10534-012-9538-6
16. Rouault TA, Zhang DL, Jeong SY (2009) Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab Brain Dis. doi:10.1007/s11011-009-9169-y
17. Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, Savoiardo M, Chiapparini L (2009) Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology 252(1):165–172. doi:10.1148/radiol.2522081399
18. Pfefferbaum A, Adalsteinsson E, Rohlfing T, Sullivan EV (2009) MRI estimates of brain iron concentration in normal aging: comparison of field-dependent (FDRI) and phase (SWI) methods. Neuroimage 47(2):493–500. doi:10.1016/j.neuroimage.2009.05.006
19. Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, Giaveri G, Arosio P, Santambrogio P, Fariello RG, Karatekin E, Kleinman MH, Turro N, Hornykiewicz O, Zucca FA (2004) The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci U S A 101(26):9843–9848. doi:10.1073/pnas.0403495101
20. Carlson ES, Fretham SJ, Unger E, O’Connor M, Petryk A, Schallert T, Rao R, Tkac I, Georgieff MK (2010) Hippocampus specific iron deficiency alters competition and cooperation between developing memory systems. J Neurodev Disord 2(3):133–143. doi:10.1007/s11689-010-9049-0
21. Carlson ES, Tkac I, Magid R, O’Connor MB, Andrews NC, Schallert T, Gunshin H, Georgieff MK, Petryk A (2009) Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr 139(4):672–679. doi:10.3945/jn.108.096354
22. Benton D (2010) The influence of dietary status on the cognitive performance of children. Mol Nutr Food Res 54(4):457–470. doi:10.1002/mnfr.200900158
23. Millichap JG (2008) Etiologic classification of attention-deficit/hyperactivity disorder. Pediatrics 121(2):e358–e365. doi:10.1542/peds.2007-1332
24. Trenkwalder C, Paulus W (2010) Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 6(6):337–346. doi:10.1038/nrneurol.2010.55
25. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81(2):871–927
26. Benarroch EE (2009) Brain iron homeostasis and neurodegenerative disease. Neurology 72(16):1436–1440. doi:10.1212/WNL.0b013e3181a26b30
27. Moos T, Morgan EH (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 20(1):77–95
28. Waheed A, Britton RS, Grubb JH, Sly WS, Fleming RE (2008) HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron. Arch Biochem Biophys 474(1):193–197. doi:10.1016/j.abb.2008.02.041
29. Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP (1999) Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 274(30):20826–20832
30. Trinder D, Baker E (2003) Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 35(3):292–296
31. Fleming RE (2009) Iron sensing as a partnership: HFE and transferrin receptor 2. Cell Metab 9(3):211–212. doi:10.1016/j.cmet.2009.02.004
32. Ganz T (2008) Iron homeostasis: fitting the puzzle pieces together. Cell Metab 7(4):288–290. doi:10.1016/j.cmet.2008.03.008
33. Kielmanowicz MG, Laham N, Coligan JE, Lemonnier F, Ehrlich R (2005) Mouse HFE inhibits Tf-uptake and iron accumulation but induces non-transferrin bound iron (NTBI)-uptake in transformed mouse fibroblasts. J Cell Physiol 202(1):105–114. doi:10.1002/jcp.20095
34. Lee PL, Beutler E (2009) Regulation of hepcidin and iron-overload disease. Annu Rev Pathol 4:489–515. doi:10.1146/annurev.pathol.4.110807.092205
35. Waheed A, Grubb JH, Zhou XY, Tomatsu S, Fleming RE, Costaldi ME, Britton RS, Bacon BR, Sly WS (2002) Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A 99(5):3117–3122. doi:10.1073/pnas.042701499
36. Lopez V, Suzuki YA, Lonnerdal B (2006) Ontogenic changes in lactoferrin receptor and DMT1 in mouse small intestine: implications for iron absorption during early life. Biochem Cell Biol 84(3):337–344. doi:10.1139/o06-059
37. Mackenzie B, Takanaga H, Hubert N, Rolfs A, Hediger MA (2007) Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J 403(1):59–69. doi:10.1042/BJ20061290
38. Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaim M, Mouren MC, Arnulf I (2008) Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol 38(1):20–26. doi:10.1016/j.pediatrneurol.2007.08.014
39. Konofal E, Cortese S, Marchand M, Mouren MC, Arnulf I, Lecendreux M (2007) Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep Med 8(7-8):711–715. doi:10.1016/j.sleep.2007.04.022
40. Sekyere EO, Dunn LL, Rahmanto YS, Richardson DR (2006) Role of melanotransferrin in iron metabolism: studies using targeted gene disruption in vivo. Blood 107(7):2599–2601. doi:10.1182/blood-2005-10-4174
41. Ben-Shachar D, Eshel G, Finberg JP, Youdim MB (1991) The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56(4):1441–1444
42. Lin AM, Ho LT (2000) Melatonin suppresses iron-induced neurodegeneration in rat brain. Free Radic Biol Med 28(6):904–911
43. Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S (2002) Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci 22(15):6578–6586, 20026652
44. Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 66(6):1198–1207. doi:10.1002/jnr.1256
45. Song N, Jiang H, Wang J, Xie JX (2007) Divalent metal transporter 1 up-regulation is involved in the 6-hydroxydopamine-induced ferrous iron influx. J Neurosci Res 85(14):3118–3126. doi:10.1002/jnr.21430
46. Lee PL, Gelbart T, West C, Halloran C, Beutler E (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 24(2):199–215. doi:10.1006/bcmd.1998.0186
47. Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A 99(19):12345–12350. doi:10.1073/pnas.192423399
48. Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan SS (2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci U S A 106(36):15489–15494. doi:10.1073/pnas.0904880106
49. Roth JA, Singleton S, Feng J, Garrick M, Paradkar PN (2010) Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1 (DMT1). J Neurochem. doi: 10.1111/j.1471-4159.2010.06607.x
50. Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM (2005) Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiol Aging 26(5):739–748. doi:10.1016/j.neurobiolaging.2004.06.002
51. Burdo JR, Martin J, Menzies SL, Dolan KG, Romano MA, Fletcher RJ, Garrick MD, Garrick LM, Connor JR (1999) Cellular distribution of iron in the brain of the Belgrade rat. Neuroscience 93(3):1189–1196
52. Hulet SW, Hess EJ, Debinski W, Arosio P, Bruce K, Powers S, Connor JR (1999) Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem 72(2):868–874
53. Chen TT, Li L, Chung DH, Allen CD, Torti SV, Torti FM, Cyster JG, Chen CY, Brodsky FM, Niemi EC, Nakamura MC, Seaman WE, Daws MR (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 202(7):955–965. doi:10.1084/jem.20042433
54. Todorich B, Zhang X, Slagle-Webb B, Seaman WE, Connor JR (2008) Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem 107(6):1495–1505. doi:10.1111/j.1471-4159.2008.05678.x
55. Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293(2):C641–C649. doi:10.1152/ajpcell.00599.2006
56. Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F, Williams D, Lin CS, Schmidt-Ott KM, Andrews NC, Barasch J (2009) Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev Cell 16(1):35–46. doi:10.1016/j.devcel.2008.12.002
57. Ganz T (2005) Cellular iron: ferroportin is the only way out. Cell Metab 1(3):155–157. doi:10.1016/j.cmet.2005.02.005
58. Kaplan J, Kushner JP (2000) Mining the genome for iron. Nature 403(6771):711–713. doi:10.1038/35001691
59. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5(2):299–309
60. Le NT, Richardson DR (2002) Ferroportin1: a new iron export molecule? Int J Biochem Cell Biol 34(2):103–108
61. Jiang DH, Ke Y, Cheng YZ, Ho KP, Qian ZM (2002) Distribution of ferroportin1 protein in different regions of developing rat brain. Dev Neurosci 24(2-3):94–98
62. Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res 1001(1-2):108–117. doi:10.1016/j.brainres.2003.10.066
63. Wang J, Jiang H, Xie JX (2007) Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. Eur J Neurosci 25(9):2766–2772. doi:10.1111/j.1460-9568.2007.05515.x
64. Morita H, Ikeda S, Yamamoto K, Morita S, Yoshida K, Nomoto S, Kato M, Yanagisawa N (1995) Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann Neurol 37(5):646–656. doi:10.1002/ana.410370515
65. Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Morita H, Hiyamuta S, Ikeda S, Shimizu N, Yanagisawa N (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9(3):267–272. doi:10.1038/ng0395-267
66. Wang J, Bi M, Xie J (2015) Ceruloplasmin is Involved in the Nigral Iron Accumulation of 6-OHDA-Lesioned Rats. Cell Mol Neurobiol 35(5):661–668. doi:10.1007/s10571-015-0161-2
67. Boll MC, Sotelo J, Otero E, Alcaraz-Zubeldia M, Rios C (1999) Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson’s disease. Neurosci Lett 265(3):155–158
68. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18(2):291–295. doi:10.1038/nm.2613
69. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142(6):857–867. doi:10.1016/j.cell.2010.08.014
70. McCarthy RC, Park YH, Kosman DJ (2014) sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep 15(7):809–815
71. Ayton S, Lei P, Hare DJ, Duce JA, George JL, Adlard PA, McLean C, Rogers JT, Cherny RA, Finkelstein DI, Bush AI (2015) Parkinson’s disease iron deposition caused by nitric oxide-induced loss of beta-amyloid precursor protein. J Neurosci 35(8):3591–3597. doi:10.1523/JNEUROSCI.3439-14.2015
72. Morris CM, Candy JM, Keith AB, Oakley AE, Taylor GA, Pullen RG, Bloxham CA, Gocht A, Edwardson JA (1992) Brain iron homeostasis. J Inorg Biochem 47(3-4):257–265
73. Levi S, Santambrogio P, Cozzi A, Rovida E, Corsi B, Tamborini E, Spada S, Albertini A, Arosio P (1994) The role of the L-chain in ferritin iron incorporation. Studies of homo and heteropolymers. J Mol Biol 238(5):649–654. doi:10.1006/jmbi.1994.1325
74. Lawson DM, Treffry A, Artymiuk PJ, Harrison PM, Yewdall SJ, Luzzago A, Cesareni G, Levi S, Arosio P (1989) Identification of the ferroxidase centre in ferritin. FEBS Lett 254(1-2):207–210
75. Cheepsunthorn P, Palmer C, Connor JR (1998) Cellular distribution of ferritin subunits in postnatal rat brain. J Comp Neurol 400(1):73–86. doi:10.1002/(SICI)1096-9861(19981012)400:1<73::AID-CNE5>3.0.CO;2-Q
76. Connor JR, Boeshore KL, Benkovic SA, Menzies SL (1994) Isoforms of ferritin have a specific cellular distribution in the brain. J Neurosci Res 37(4):461–465. doi:10.1002/jnr.490370405
77. Snyder AM, Connor JR (2009) Iron, the substantia nigra and related neurological disorders. Biochim Biophys Acta 1790(7):606–614. doi:10.1016/j.bbagen.2008.08.005
78. Han J, Day JR, Connor JR, Beard JL (2002) H and L ferritin subunit mRNA expression differs in brains of control and iron-deficient rats. J Nutr 132(9):2769–2774
79. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ (2003) Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61(3):304–309
80. Double KL, Gerlach M, Schunemann V, Trautwein AX, Zecca L, Gallorini M, Youdim MB, Riederer P, Ben-Shachar D (2003) Iron-binding characteristics of neuromelanin of the human substantia nigra. Biochem Pharmacol 66(3):489–494
81. Tribl F, Asan E, Arzberger T, Tatschner T, Langenfeld E, Meyer HE, Bringmann G, Riederer P, Gerlach M, Marcus K (2009) Identification of L-ferritin in neuromelanin granules of the human substantia nigra: a targeted proteomics approach. Mol Cell Proteomics 8(8):1832–1838. doi:10.1074/mcp.M900006-MCP200
82. Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, Jonneaux A, Ryckewaert G, Garcon G, Rouaix N, Duhamel A, Jissendi P, Dujardin K, Auger F, Ravasi L, Hopes L, Grolez G, Firdaus W, Sablonniere B, Strubi-Vuillaume I, Zahr N, Destee A, Corvol JC, Poltl D, Leist M, Rose C, Defebvre L, Marchetti P, Cabantchik ZI, Bordet R (2014) Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21(2):195–210. doi:10.1089/ars.2013.5593
83. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276(11):7806–7810. doi:10.1074/jbc.M008922200
84. Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S (2002) Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 29(3):327–335
85. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704):2090–2093. doi:10.1126/science.1104742
86. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M (2005) Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci U S A 102(5):1324–1328. doi:10.1073/pnas.0409409102
87. Wang SM, Fu LJ, Duan XL, Crooks DR, Yu P, Qian ZM, Di XJ, Li J, Rouault TA, Chang YZ (2009) Role of hepcidin in murine brain iron metabolism. Cell Mol Life Sci. doi:10.1007/s00018-009-0167-3
88. Zechel S, Huber-Wittmer K, Von B, Halbach O (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res 84(4):790–800. doi:10.1002/jnr.20991
89. Du F, Qian ZM, Luo Q, Yung WH, Ke Y (2014) Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats. Mol Neurobiol. doi:10.1007/s12035-014-8847-x
90. Foot NJ, Dalton HE, Shearwin-Whyatt LM, Dorstyn L, Tan SS, Yang B, Kumar S (2008) Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 112(10):4268–4275. doi:10.1182/blood-2008-04-150953
91. Guo B, Yu Y, Leibold EA (1994) Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J Biol Chem 269(39):24252–24260
92. Henderson BR, Kuhn LC (1995) Differential modulation of the RNA-binding proteins IRP-1 and IRP-2 in response to iron. IRP-2 inactivation requires translation of another protein. J Biol Chem 270(35):20509–20515
93. Regan RF, Li Z, Chen M, Zhang X, Chen-Roetling J (2008) Iron regulatory proteins increase neuronal vulnerability to hydrogen peroxide. Biochem Biophys Res Commun 375(1):6–10. doi:10.1016/j.bbrc.2008.07.061
94. Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Suryo Rahmanto Y, Sheftel AD, Ponka P (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci U S A 107(24):10775–10782. doi:10.1073/pnas.0912925107
95. Yanatori I, Tabuchi M, Kawai Y, Yasui Y, Akagi R, Kishi F (2010) Heme and non-heme iron transporters in non-polarized and polarized cells. BMC Cell Biol 11:39. doi:10.1186/1471-2121-11-39
96. Zhang Y, Mikhael M, Xu D, Li Y, Soe-Lin S, Ning B, Li W, Nie G, Zhao Y, Ponka P (2010a) Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. Antioxid Redox Signal 13(7):999–1009. doi:10.1089/ars.2010.3129
97. Zhang J, Zhang Y, Wang J, Cai P, Luo C, Qian Z, Dai Y, Feng H (2010b) Characterizing iron deposition in Parkinson's disease using susceptibility-weighted imaging: an in vivo MR study. Brain Res 2010; 1330:124--130
98. Garrick MD, Zhao L, Roth JA, Jiang H, Feng J, Foot NJ, Dalton H, Kumar S, Garrick LM (2012) Isoform specific regulation of divalent metal (ion) transporter (DMT1) by proteasomal degradation. Biometals 25(4):787–793. doi:10.1007/s10534-012-9522-1
99. Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK (2009) The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem 110(2):719–733. doi:10.1111/j.1471-4159.2009.06165.x
100. Dong XP, 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(7215):992–996. doi:10.1038/nature07311
101. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87(1):165–217. doi:10.1152/physrev.00021.2006
102. Qian F, Noben-Trauth K (2005) Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2). Pflugers Arch 451(1):277–285. doi:10.1007/s00424-005-1469-4
103. Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS Jr, Bove C, Kaneski CR, Nagle J, Bromley MC, Colman M, Schiffmann R, Slaugenhaupt SA (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet 9(17):2471–2478
104. Napier I, Ponka P, Richardson DR (2005) Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 105(5):1867–1874. doi:10.1182/blood-2004-10-3856
105. Huang XP, O’Brien PJ, Templeton DM (2006) Mitochondrial involvement in genetically determined transition metal toxicity I. Iron toxicity. Chem Biol Interact 163(1-2):68–76. doi:10.1016/j.cbi.2006.05.007
106. Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, Na HM, Gutekunst CA, Gearing M, Trojanowski JQ, Anderson M, Chu CT, Peng J, Greenamyre JT (2009) A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson’s disease. Neurobiol Dis 34(3):417–431. doi:10.1016/j.nbd.2009.02.009
107. Rhodes SL, Buchanan DD, Ahmed I, Taylor KD, Loriot MA, Sinsheimer JS, Bronstein JM, Elbaz A, Mellick GD, Rotter JI, Ritz B (2014) Pooled analysis of iron-related genes in Parkinson’s disease: association with transferrin. Neurobiol Dis 62:172–178. doi:10.1016/j.nbd.2013.09.019
108. Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J (2001) A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276(27):24437–24440. doi:10.1074/jbc.C100141200
109. Jin L, Wang J, Zhao L, Jin H, Fei G, Zhang Y, Zeng M, Zhong C (2011) Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson’s disease. Brain 134(Pt 1):50–58. doi:10.1093/brain/awq319
110. Missirlis F, Holmberg S, Georgieva T, Dunkov BC, Rouault TA, Law JH (2006) Characterization of mitochondrial ferritin in Drosophila. Proc Natl Acad Sci U S A 103(15):5893–5898. doi:10.1073/pnas.0601471103
111. Shi ZH, Nie G, Duan XL, Rouault T, Wu WS, Ning B, Zhang N, Chang YZ, Zhao BL (2010) Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson’s disease. Antioxid Redox Signal 13(6):783–796. doi:10.1089/ars.2009.3018
112. Bandyopadhyay S, Cahill C, Balleidier A, Huang C, Lahiri DK, Huang X, Rogers JT (2013) Novel 5’ untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for down syndrome and Alzheimer’s disease. PLoS One 8(7):e65978. doi:10.1371/journal.pone.0065978
113. Santambrogio P, Biasiotto G, Sanvito F, Olivieri S, Arosio P, Levi S (2007) Mitochondrial ferritin expression in adult mouse tissues. J Histochem Cytochem 55(11):1129–1137
114. Bou-Abdallah F, Santambrogio P, Levi S, Arosio P, Chasteen ND (2005) Unique iron binding and oxidation properties of human mitochondrial ferritin: a comparative analysis with Human H-chain ferritin. J Mol Biol 347(3):543–554. doi:10.1016/j.jmb.2005.01.007
115. Nie G, Sheftel AD, Kim SF, Ponka P (2005) Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105(5):2161–2167. doi:10.1182/blood-2004-07-2722
116. Wu WS, Zhao YS, Shi ZH, Chang SY, Nie GJ, Duan XL, Zhao SM, Wu Q, Yang ZL, Zhao BL, Chang YZ (2013) Mitochondrial ferritin attenuates beta-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways. Antioxid Redox Signal 18(2):158–169. doi:10.1089/ars.2011.4285
117. Schipper HM (2004) Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med 37(12):1995–2011. doi:10.1016/j.freeradbiomed.2004.09.015
118. Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper HM (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J Neurochem 77(5):1386–1395
119. Lavrovsky Y, Drummond GS, Abraham NG (1996) Downregulation of the human heme oxygenase gene by glucocorticoids and identification of 56b regulatory elements. Biochem Biophys Res Commun 218(3):759–765. doi:10.1006/bbrc.1996.0135
120. Broekemeier KM, Pfeiffer DR (1995) Inhibition of the mitochondrial permeability transition by cyclosporin A during long time frame experiments: relationship between pore opening and the activity of mitochondrial phospholipases. Biochemistry 34(50):16440–16449
121. Petronilli V, Cola C, Massari S, Colonna R, Bernardi P (1993) Physiological effectors modify voltage sensing by the cyclosporin A-sensitive permeability transition pore of mitochondria. J Biol Chem 268(29):21939–21945
122. Song L, Song W, Schipper HM (2007) Astroglia overexpressing heme oxygenase-1 predispose co-cultured PC12 cells to oxidative injury. J Neurosci Res 85(10):2186–2195. doi:10.1002/jnr.21367
123. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52(2):515–520
124. Mann VM, Cooper JM, Daniel SE, Srai K, Jenner P, Marsden CD, Schapira AH (1994) Complex I, iron, and ferritin in Parkinson's disease substantia nigra. Ann Neurol 36(6):876–881
125. Griffiths PD, Dobson BR, Jones GR, Clarke DT (1999) Iron in the basal ganglia in Parkinson's disease. An in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy. Brain 122(4):667–673
126. Jellinger K, Kienzl E, Rumpelmair G, Riederer P, Stachelberger H, Ben-Shachar D, Youdim MB (1992) Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J Neurochem 59(3):1168–1171
127. Berg, D., Roggendorf, W., Schroder, U., Klein, R., Tatschner, T., Benz, P., Tucha, O., Preier, M., Lange, K. W., Reiners, K., Gerlach, M. and Becker, G. (2002) Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59:999–1005
128. Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37(6):899–909
129. Gaeta A, Hider RC (2005) The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy. Br J Pharmacol 146(8):1041–1059. doi:10.1038/sj.bjp.0706416
130. Zhu W, Xie W, Pan T, Xu P, Fridkin M, Zheng H, Jankovic J, Youdim MB, Le W (2007) Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. FASEB J 21(14):3835–3844. doi:10.1096/fj.07-8386com
131. Youdim MB (2006) My love with monoamine oxidase, iron and Parkinson’s disease. J Neural Transm Suppl 71:V–IX
132. Ayton S, Lei P, Adlard PA, Volitakis I, Cherny RA, Bush AI, Finkelstein DI (2014) Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease. Mol Neurodegener 9:27. doi:10.1186/1750-1326-9-27
133. Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74(3):199–205
134. Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MB (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56(3):978–982
135. Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (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
136. Drayer BP, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer S (1986) Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 159(2):493–498
137. Ryvlin P, Broussolle E, Piollet H, Viallet F, Khalfallah Y, Chazot G (1995) Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson’s disease. Arch Neurol 52(6):583–588
138. Good PF, Olanow CW, Perl DP (1992) Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study. Brain Res 593(2):343–346
139. Bandyopadhyay S, Rogers JT (2014) Alzheimer’s disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis. Biochem Pharmacol 88(4):486–494. doi:10.1016/j.bcp.2014.01.032
140. Rossi M, Ruottinen H, Soimakallio S, Elovaara I, Dastidar P (2013) Clinical MRI for iron detection in Parkinson’s disease. Clin Imaging 37(4):631–636. doi:10.1016/j.clinimag.2013.02.001
141. Wang C, Fan G, Xu K, Wang S (2013) Quantitative assessment of iron deposition in the midbrain using 3D-enhanced T2 star weighted angiography (ESWAN): a preliminary cross-sectional study of 20 Parkinson’s disease patients. Magn Reson Imaging 31(7):1068–1073. doi:10.1016/j.mri.2013.04.015
142. Barbosa JH, Santos AC, Tumas V, Liu M, Zheng W, Haacke EM, Salmon CE (2015) Quantifying brain iron deposition in patients with Parkinson’s disease using quantitative susceptibility mapping, R2 and R2. Magn Reson Imaging 33(5):559–565. doi:10.1016/j.mri.2015.02.021
143. Berg D (2006) In vivo detection of iron and neuromelanin by transcranial sonography--a new approach for early detection of substantia nigra damage. J Neural Transm 113(6):775–780. doi:10.1007/s00702-005-0447-5
144. Wallis LI, Paley MN, Graham JM, Grunewald RA, Wignall EL, Joy HM, Griffiths PD (2008) MRI assessment of basal ganglia iron deposition in Parkinson’s disease. J Magn Reson Imaging 28(5):1061–1067. doi:10.1002/jmri.21563
145. Pavese N, Brooks DJ (2008) Imaging neurodegeneration in Parkinson’s disease. Biochimica et biophysica acta. doi: 10.1016/j.bbadis.2008.10.003
146. Martin WR, Wieler M, Gee M (2008) Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 70(16 Pt 2):1411–1417. doi:10.1212/01.wnl.0000286384.31050.b5
147. Pavese N, Brooks DJ (2009) Imaging neurodegeneration in Parkinson’s disease. Biochim Biophys Acta 1792(7):722–729. doi:10.1016/j.bbadis.2008.10.003
148. Wu SF, Zhu ZF, Kong Y, Zhang HP, Zhou GQ, Jiang QT, Meng XP (2014) Assessment of cerebral iron content in patients with Parkinson’s disease by the susceptibility-weighted MRI. Eur Rev Med Pharmacol Sci 18(18):2605–2608
149. Yu X, Du T, Song N, He Q, Shen Y, Jiang H, Xie J (2013) Decreased iron levels in the temporal cortex in postmortem human brains with Parkinson disease. Neurology 80(5):492–495. doi:10.1212/WNL.0b013e31827f0ebb
150. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ (1999) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology 20(2-3):239–247
151. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2003) Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 60(11):1761–1766
152. Logroscino G, Gao X, Chen H, Wing A, Ascherio A (2008) Dietary iron intake and risk of Parkinson’s disease. Am J Epidemiol 168(12):1381–1388. doi:10.1093/aje/kwn273
153. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease. Parkinsonism Relat Disord 15(1):47–52. doi:10.1016/j.parkreldis.2008.03.002
154. Ma ZG, Wang J, Jiang H, Liu TW, Xie JX (2007) Myricetin reduces 6-hydroxydopamine-induced dopamine neuron degeneration in rats. Neuroreport 18(11):1181–1185. doi:10.1097/WNR.0b013e32821c51fe
155. Wang J, Jiang H, Xie JX (2004) Time dependent effects of 6-OHDA lesions on iron level and neuronal loss in rat nigrostriatal system. Neurochem Res 29(12):2239–2243
156. Wang J, Xu HM, Yang HD, Du XX, Jiang H, Xie JX (2009) Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins. Neurochem Int 54(1):43–48. doi:10.1016/j.neuint.2008.10.003
157. Youdim MB (2003) What have we learnt from CDNA microarray gene expression studies about the role of iron in MPTP induced neurodegeneration and Parkinson’s disease? J Neural Transm Suppl 65:73–88
158. Youdim MB, 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(7-8):679–689. doi:10.1080/1029842021000045507
159. Hare DJ, Adlard PA, Doble PA, Finkelstein DI (2013) Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Metallomics 5(2):91–109. doi:10.1039/c2mt20164j
160. Zhang J, Stanton DM, Nguyen XV, Liu M, Zhang Z, Gash D, Bing G (2005) Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits. Neuroscience 135(3):829–838. doi:10.1016/j.neuroscience.2005.06.049
161. Peng J, Peng L, Stevenson FF, Doctrow SR, Andersen JK (2007) Iron and paraquat as synergistic environmental risk factors in sporadic Parkinson’s disease accelerate age-related neurodegeneration. J Neurosci 27(26):6914–6922. doi:10.1523/JNEUROSCI.1569-07.2007
162. Peng J, Stevenson FF, Oo ML, Andersen JK (2009) Iron-enhanced paraquat-mediated dopaminergic cell death due to increased oxidative stress as a consequence of microglial activation. Free Radic Biol Med 46(2):312–320. doi:10.1016/j.freeradbiomed.2008.10.045
163. Junxia X, Hong J, Wenfang C, Ming Q (2003) Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of Parkinson’s disease. Exp Neurol 182(2):483–489
164. Ben-Shachar D, Youdim MB (1991) Intranigral iron injection induces behavioral and biochemical “parkinsonism” in rats. J Neurochem 57(6):2133–2135
165. Jiang H, Song N, Wang J, Ren LY, Xie JX (2007) Peripheral iron dextran induced degeneration of dopaminergic neurons in rat substantia nigra. Neurochem Int 51(1):32–36. doi:10.1016/j.neuint.2007.03.006
166. Jiang H, Luan Z, Wang J, Xie J (2006) Neuroprotective effects of iron chelator Desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem Int 49(6):605–609. doi:10.1016/j.neuint.2006.04.015
167. Fredriksson A, Schroder N, Eriksson P, Izquierdo I, Archer T (1999) Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice. Toxicol Appl Pharmacol 159(1):25–30. doi:10.1006/taap.1999.8711
168. Kaur D, Peng J, Chinta SJ, Rajagopalan S, Di Monte DA, Cherny RA, Andersen JK (2007) Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging 28(6):907–913. doi:10.1016/j.neurobiolaging.2006.04.003
169. Faucheux BA, Hirsch EC, Villares J, Selimi F, Mouatt-Prigent A, Javoy-Agid F, Hauw JJ, Agid Y (1993) Distribution of 125I-ferrotransferrin binding sites in the mesencephalon of control subjects and patients with Parkinson's disease. J Neurochem 60: 2338–2341
170. Faucheux BA, Hauw JJ, Agid Y, Hirsch EC (1997) The density of [125I]-transferrin binding sites on perikarya of melanized neurons of the substantia nigra is decreased in Parkinson’s disease. Brain Res 749(1):170–174
171. Kalivendi SV, Kotamraju S, Cunningham S, Shang T, Hillard CJ, Kalyanaraman B (2003) 1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. Biochem J 371(Pt 1):151–164. doi:10.1042/BJ20021525
172. Kaur D, Lee D, Ragapolan S, Andersen JK (2009) Glutathione depletion in immortalized midbrain-derived dopaminergic neurons results in increases in the labile iron pool: implications for Parkinson’s disease. Free Radic Biol Med 46(5):593–598. doi:10.1016/j.freeradbiomed.2008.11.012
173. Lee DW, Andersen JK (2010) Iron elevations in the aging Parkinsonian brain: a consequence of impaired iron homeostasis? J Neurochem 112(2):332–339. doi:10.1111/j.1471-4159.2009.06470.x
174. Huang E, Ong WY, Connor JR (2004) Distribution of divalent metal transporter-1 in the monkey basal ganglia. Neuroscience 128(3):487–496. doi:10.1016/j.neuroscience.2004.06.055
175. Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nunez MT, Garrick MD, Raisman-Vozari R, Hirsch EC (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci U S A 105(47):18578–18583. doi:10.1073/pnas.0804373105
176. Chung J, Wessling-Resnick M (2003) Molecular mechanisms and regulation of iron transport. Crit Rev Clin Lab Sci 40(2):151–182
177. Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, Hentze MW, Rouault TA, Andrews NC, Hediger MA (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 509(2):309–316
178. Song N, Wang J, Jiang H, Xie J Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson's disease. Free Radic Biol Med 48 (2):332-341. doi: 10.1016/j.freeradbiomed.2009.11.004
179. Jiang H, Qian ZM, Xie JX (2003) Increased DMT1 expression and iron content in MPTP-treated C57BL/6 mice. Sheng Li Xue Bao 55(5):571–576
180. Lee DW, Rajagopalan S, Siddiq A, Gwiazda R, Yang L, Beal MF, Ratan RR, Andersen JK (2009) Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem 284(42):29065–29076. doi:10.1074/jbc.M109.000638
181. Xu H, Jiang H, Wang J, Xie J (2009) Rg1 protects the MPP(+)-treated MES23.5 cells via attenuating DMT1 up-regulation and cellular iron uptake. Neuropharmacology. doi: 10.1016/j.neuropharm.2009.09.002
182. Zhang S, Wang J, Song N, Xie J, Jiang H (2009) Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol Aging 30(9):1466–1476. doi:10.1016/j.neurobiolaging.2007.11.025
183. Xu HM, Jiang H, Wang J, Luo B, Xie JX (2008) Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells. Neurochem Int 52(6):1044–1051. doi:10.1016/j.neuint.2007.10.019
184. van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK (2001) Antiviral activities of lactoferrin. Antiviral Res 52(3):225–239
185. Fillebeen C, Ruchoux MM, Mitchell V, Vincent S, Benaissa M, Pierce A (2001) Lactoferrin is synthesized by activated microglia in the human substantia nigra and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment. Brain Res Mol Brain Res 96(1-2):103–113
186. Fillebeen C, Mitchell V, Dexter D, Benaissa M, Beauvillain J, Spik G, Pierce A (1999) Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. Brain Res Mol Brain Res 72(2):183–194
187. Leveugle B, Faucheux BA, Bouras C, Nillesse N, Spik G, Hirsch EC, Agid Y, Hof PR (1996) Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol 91(6):566–572
188. Faucheux BA, Nillesse N, Damier P, Spik G, Mouatt-Prigent A, Pierce A, Leveugle B, Kubis N, Hauw JJ, Agid Y et al (1995) Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. Proc Natl Acad Sci U S A 92(21):9603–9607
189. De Domenico I, Ward DM, di Patti MC, Jeong SY, 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(12):2823–2831. doi:10.1038/sj.emboj.7601735
190. Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL (2004) 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(38):13850–13855. doi:10.1073/pnas.0405146101
191. Kaneko K, Hineno A, Yoshida K, Ikeda S (2008) Increased vulnerability to rotenone-induced neurotoxicity in ceruloplasmin-deficient mice. Neurosci Lett 446(1):56–58. doi:10.1016/j.neulet.2008.08.089
192. Bharucha KJ, Friedman JK, Vincent AS, Ross ED (2008) Lower serum ceruloplasmin levels correlate with younger age of onset in Parkinson’s disease. J Neurol 255(12):1957–1962. doi:10.1007/s00415-009-0063-7
193. Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J (2005) CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14(1):43–47. doi:10.1111/j.1365-2869.2004.00403.x
194. Tapryal N, Mukhopadhyay C, Das D, Fox PL, Mukhopadhyay CK (2009) Reactive oxygen species regulate ceruloplasmin by a novel mRNA decay mechanism involving its 3’-untranslated region: implications in neurodegenerative diseases. J Biol Chem 284(3):1873–1883. doi:10.1074/jbc.M804079200
195. Ayton S, Lei P, Duce JA, Wong BX, Sedjahtera A, Adlard PA, Bush AI, Finkelstein DI (2013) Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 73(4):554–559. doi:10.1002/ana.23817
196. Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, Fasano M (2004) Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4(12):3943–3952. doi:10.1002/pmic.200400848
197. Tsushima RG, Wickenden AD, Bouchard RA, Oudit GY, Liu PP, Backx PH (1999) Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload. Circ Res 84(11):1302–1309
198. Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP, Backx PH (2003) L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 9(9):1187–1194. doi:10.1038/nm920
199. De Waard M, Gurnett CA, Campbell KP (1996) Structural and functional diversity of voltage-activated calcium channels. Ion Channels 4:41–87
200. Gaasch JA, Geldenhuys WJ, Lockman PR, Allen DD, Van der Schyf CJ (2007) Voltage-gated calcium channels provide an alternate route for iron uptake in neuronal cell cultures. Neurochem Res 32(10):1686–1693. doi:10.1007/s11064-007-9313-1
201. Liss B, Roeper J (2001) ATP-sensitive potassium channels in dopaminergic neurons: transducers of mitochondrial dysfunction. News Physiol Sci 16:214–217
202. Liss B, Haeckel O, Wildmann J, Miki T, Seino S, Roeper J (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8(12):1742–1751. doi:10.1038/nn1570
203. Schiemann J, Schlaudraff F, Klose V, Bingmer M, Seino S, Magill PJ, Zaghloul KA, Schneider G, Liss B, Roeper J (2012) K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat Neurosci 15(9):1272–1280. doi:10.1038/nn.3185
204. Li YX, Bertram R, Rinzel J (1996) Modeling N-methyl-D-aspartate-induced bursting in dopamine neurons. Neuroscience 71(2):397–410
205. Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (2007) ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 447(7148):1081–1086. doi:10.1038/nature05865
206. Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468(7324):696–700. doi:10.1038/nature09536
207. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388(6641):482–488. doi:10.1038/41343
208. Olanow CW (1992) An introduction to the free radical hypothesis in Parkinson’s disease. Ann Neurol 32(Suppl):S2–S9
209. Cantuti-Castelvetri I, Shukitt-Hale B, Joseph JA (2003) Dopamine neurotoxicity: age-dependent behavioral and histological effects. Neurobiol Aging 24(5):697–706
210. Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30(5):244–250. doi:10.1016/j.tins.2007.03.009
211. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3(3):205–214. doi:10.1038/nrd1330
212. Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3(12):932–942. doi:10.1038/nrn983
213. Jimenez-Jimenez FJ, Molina JA, Aguilar MV, Meseguer I, Mateos-Vega CJ, Gonzalez-Munoz MJ, de Bustos F, Martinez-Salio A, Orti-Pareja M, Zurdo M, Martinez-Para MC (1998) Cerebrospinal fluid levels of transition metals in patients with Parkinson’s disease. J Neural Transm 105(4-5):497–505
214. He Y, Thong PS, Lee T, Leong SK, Shi CY, Wong PT, Yuan SY, Watt F (1996) Increased iron in the substantia nigra of 6-OHDA induced parkinsonian rats: a nuclear microscopy study. Brain Res 735(1):149–153
215. Popescu BF, George MJ, Bergmann U, Garachtchenko AV, Kelly ME, McCrea RP, Luning K, Devon RM, George GN, Hanson AD, Harder SM, Chapman LD, Pickering IJ, Nichol H (2009) Mapping metals in Parkinson’s and normal brain using rapid-scanning x-ray fluorescence. Phys Med Biol 54(3):651–663. doi:10.1088/0031-9155/54/3/012
216. Fasano M, Bergamasco B, Lopiano L (2006) Modifications of the iron-neuromelanin system in Parkinson’s disease. J Neurochem 96(4):909–916. doi:10.1111/j.1471-4159.2005.03638.x
217. Berg D, Gerlach M, Youdim MB, Double KL, Zecca L, Riederer P, Becker G (2001) Brain iron pathways and their relevance to Parkinson’s disease. J Neurochem 79(2):225–236
218. Zecca L, Zucca FA, Albertini A, Rizzio E, Fariello RG (2006) A proposed dual role of neuromelanin in the pathogenesis of Parkinson’s disease. Neurology 67(7 Suppl 2):S8–S11
219. Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T (2008) Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J Neurochem 106(4):1866–1875. doi:10.1111/j.1471-4159.2008.05541.x
220. 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(3):216–220
221. Muller M, Leavitt BR (2014) Iron dysregulation in Huntington’s disease. J Neurochem 130(3):328–350. doi:10.1111/jnc.12739
222. Forno LS, DeLanney LE, Irwin I, Di Monte D, Langston JW (1992) Astrocytes and Parkinson’s disease. Prog Brain Res 94:429–436
223. Oshiro S, Kawamura K, Zhang C, Sone T, Morioka MS, Kobayashi S, Nakajima K (2008) Microglia and astroglia prevent oxidative stress-induced neuronal cell death: implications for aceruloplasminemia. Biochim Biophys Acta 1782(2):109–117. doi:10.1016/j.bbadis.2007.12.002
224. Oshiro S, Kawahara M, Kuroda Y, Zhang C, Cai Y, Kitajima S, Shirao M (2000) Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells. Biochim Biophys Acta 1502(3):405–414
225. Kress GJ, Dineley KE, Reynolds IJ (2002) The relationship between intracellular free iron and cell injury in cultured neurons, astrocytes, and oligodendrocytes. J Neurosci 22(14):5848–5855, 20026601
226. Hoepken HH, Korten T, Robinson SR, Dringen R (2004) Iron accumulation, iron-mediated toxicity and altered levels of ferritin and transferrin receptor in cultured astrocytes during incubation with ferric ammonium citrate. J Neurochem 88(5):1194–1202
227. Raicevic N, Mladenovic A, Perovic M, Harhaji L, Miljkovic D, Trajkovic V (2005) Iron protects astrocytes from 6-hydroxydopamine toxicity. Neuropharmacology 48(5):720–731. doi:10.1016/j.neuropharm.2004.12.003
228. Burdo JR, Connor JR (2003) Brain iron uptake and homeostatic mechanisms: an overview. Biometals 16(1):63–75
229. Bush AI (2000) Metals and neuroscience. Curr Opin Chem Biol 4(2):184–191
230. Berg D, Hochstrasser H (2006) Iron metabolism in Parkinsonian syndromes. Mov Disord 21(9):1299–1310. doi:10.1002/mds.21020
231. Reif DW (1992) Ferritin as a source of iron for oxidative damage. Free Radic Biol Med 12(5):417–427
232. Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6(5):513–519. doi:10.1038/74994
233. Simpkins JW, Dykens JA (2008) Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev 57(2):421–430. doi:10.1016/j.brainresrev.2007.04.007
234. Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B (2005) Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 280(52):42655–42668. doi:10.1074/jbc.M505910200
235. Ikeda Y, Tsuji S, Satoh A, Ishikura M, Shirasawa T, Shimizu T (2008) Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J Neurochem 107(6):1730–1740. doi:10.1111/j.1471-4159.2008.05743.x
236. Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T, Yin XM, Chen J (2007) Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem 282(47):34479–34491. doi:10.1074/jbc.M705426200
237. Double KL, Maywald M, Schmittel M, Riederer P, Gerlach M (1998) In vitro studies of ferritin iron release and neurotoxicity. J Neurochem 70(6):2492–2499
238. Zhang X, Xie W, Qu S, Pan T, Wang X, Le W (2005) Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration. Biochem Biophys Res Commun 333(2):544–549. doi:10.1016/j.bbrc.2005.05.150
239. McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, Jennert P, Olanow CW (2002) Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81(2):301–306
240. Zhu W, Li X, Xie W, Luo F, Kaur D, Andersen JK, Jankovic J, Le W (2010) Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration. Neurobiol Dis 37(2):307–313. doi:10.1016/j.nbd.2009.09.024
241. Wang J, Fillebeen C, Chen G, Biederbick A, Lill R, Pantopoulos K (2007) Iron-dependent degradation of apo-IRP1 by the ubiquitin-proteasome pathway. Mol Cell Biol 27(7):2423–2430. doi:10.1128/MCB.01111-06
242. Jia W, Xu H, Du X, Jiang H, Xie J (2015) Ndfip1 attenuated 6-OHDA-induced iron accumulation via regulating the degradation of DMT1. Neurobiol Aging 36(2):1183–1193. doi:10.1016/j.neurobiolaging.2014.10.021
243. Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL (1999) alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson’s disease. J Biol Chem 274(28):19509–19512
244. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18(2):106–108. doi:10.1038/ng0298-106
245. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047
246. Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56(2):446–451
247. Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross CA, Kretzschmar H, Giese A (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283(16):10992–11003. doi:10.1074/jbc.M709634200
248. Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103(1):17–37. doi:10.1111/j.1471-4159.2007.04764.x
249. Cole NB, Murphy DD, Lebowitz J, Di Noto L, Levine RL, Nussbaum RL (2005) Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem 280(10):9678–9690. doi:10.1074/jbc.M409946200
250. Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem 277(18):16116–16123. doi:10.1074/jbc.M107866200
251. Davies P, Moualla D, Brown DR (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One 6(1):e15814. doi:10.1371/journal.pone.0015814
252. Brown DR (2013) alpha-Synuclein as a ferrireductase. Biochem Soc Trans 41(6):1513–1517. doi:10.1042/BST20130130
253. Ortega R, Carmona A, Roudeau S, Perrin L, Ducic T, Carboni E, Bohic S, Cloetens P, Lingor P (2015) alpha-Synuclein Over-Expression Induces Increased Iron Accumulation and Redistribution in Iron-Exposed Neurons. Mol Neurobiol. doi:10.1007/s12035-015-9146-x
254. Friedlich AL, Tanzi RE, Rogers JT (2007) The 5’-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry 12(3):222–223. doi:10.1038/sj.mp.4001937
255. Olivares D, Huang X, Branden L, Greig NH, Rogers JT (2009) Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element. Int J Mol Sci 10(3):1226–1260. doi:10.3390/ijms10031226
256. Zhu ZJ, Wu KC, Yung WH, Qian ZM, Ke Y (2016) Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila. Biochim Biophys Acta 1862(4):518–525. doi:10.1016/j.bbadis.2016.01.002
257. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28(4):350–354. doi:10.1038/ng571
258. Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD (1995) Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A 92(7):2539–2543
259. Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism. Nature 440(7083):470–476. doi:10.1038/nature04711
260. Thomzig A, Pruss H, Veh RW (2003) The Kir6.1-protein, a pore-forming subunit of ATP-sensitive potassium channels, is prominently expressed by giant cholinergic interneurons in the striatum of the rat brain. Brain Res 986(1-2):132–138
261. Holemans S, Javoy-Agid F, Agid Y, De Paermentier F, Laterre EC, Maloteaux JM (1994) Sulfonylurea binding sites in normal human brain and in Parkinson’s disease, progressive supranuclear palsy and Huntington’s disease. Brain Res 642(1-2):327–333
262. Takanashi M, Mochizuki H, Yokomizo K, Hattori N, Mori H, Yamamura Y, Mizuno Y (2001) Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP). Parkinsonism Relat Disord 7(4):311–314
263. Altamura S, Muckenthaler MU (2009) Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis 16(4):879–895. doi:10.3233/JAD-2009-1010
264. Antharam V, Collingwood JF, Bullivant JP, Davidson MR, Chandra S, Mikhaylova A, Finnegan ME, Batich C, Forder JR, Dobson J (2012) High field magnetic resonance microscopy of the human hippocampus in Alzheimer’s disease: quantitative imaging and correlation with iron. Neuroimage 59(2):1249–1260. doi:10.1016/j.neuroimage.2011.08.019
265. Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP (2004) Role of dietary iron restriction in a mouse model of Parkinson’s disease. Exp Neurol 190(2):506–514. doi:10.1016/j.expneurol.2004.08.014
266. Shoham S, Youdim MB (2004) Nutritional iron deprivation attenuates kainate-induced neurotoxicity in rats: implications for involvement of iron in neurodegeneration. Ann N Y Acad Sci 1012:94–114
267. Dexter DT, Statton SA, Whitmore C, Freinbichler W, Weinberger P, Tipton KF, Della Corte L, Ward RJ, Crichton RR (2011) Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson’s disease after peripheral administration. J Neural Transm 118(2):223–231. doi:10.1007/s00702-010-0531-3
268. Bar-Am O, Amit T, Kupershmidt L, Aluf Y, Mechlovich D, Kabha H, Danovitch L, Zurawski VR, Youdim MB, Weinreb O (2015) Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson’s disease and aging. Neurobiol Aging 36(3):1529–1542. doi:10.1016/j.neurobiolaging.2014.10.026
269. Kalfon L, Youdim MB, Mandel SA (2007) Green tea polyphenol (-) -epigallocatechin-3-gallate promotes the rapid protein kinase C- and proteasome-mediated degradation of Bad: implications for neuroprotection. J Neurochem 100(4):992–1002. doi:10.1111/j.1471-4159.2006.04265.x
270. Wang J, Du XX, Jiang H, Xie JX (2009) Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-oxidation and nuclear factor-kappa B modulation in MES23.5 cells. Biochem Pharmacol 78(2):178–183. doi:10.1016/j.bcp.2009.03.031
271. Wang YQ, Wang MY, Fu XR, Peng Y, Gao GF, Fan YM, Duan XL, Zhao BL, Chang YZ, Shi ZH (2015) Neuroprotective effects of ginkgetin against neuroinjury in Parkinson’s disease model induced by MPTP via chelating iron. Free Radic Res:1-12. doi:10.3109/10715762.2015.1032958
272. Beard JL, Erikson KM, Jones BC (2002) Neurobehavioral analysis of developmental iron deficiency in rats. Behav Brain Res 134(1-2):517–524
273. Erikson KM, Jones BC, Beard JL (2000) Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 130(11):2831–2837
274. Youdim MB (2008) Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus. Neurotox Res 14(1):45–56
275. Beard J, Erikson KM, Jones BC (2003) Neonatal iron deficiency results in irreversible changes in dopamine function in rats. J Nutr 133(4):1174–1179
276. Unger EL, Paul T, Murray-Kolb LE, Felt B, Jones BC, Beard JL (2007) Early iron deficiency alters sensorimotor development and brain monoamines in rats. J Nutr 137(1):118–124
277. Doraiswamy PM, Finefrock AE (2004) Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol 3(7):431–434. doi:10.1016/S1474-4422(04)00809-9
278. Song N, Wang J, Jiang H, Xie J (2010) Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson’s disease. Free Radic Biol Med 48(2):332–341. doi:10.1016/j.freeradbiomed.2009.11.004