Skip to main content
SpringerLink
Log in

Iron dyshomeostasis in Parkinson’s disease

  • Chapter
Oxidative Stress and Neuroprotection

Part of the book series: Journal of Neural Transmission. Supplementa ((NEURALTRANS,volume 71))

Summary

Owing to its ability to undergo one-electron reactions, iron transforms the mild oxidant hydrogen peroxide into hydroxyl radical, one of the most reactive species in nature. Deleterious effects of iron accumulation are dramatically evidenced in several neurodegenerative diseases. The work of Youdim and collaborators has been fundamental in describing the accumulation of iron confined to the substantia nigra (SN) in Parkinson’s disease (PD) and to clarify iron toxicity pathways and oxidative damage in dopaminergic neurons. Nevertheless, how the mechanisms involved in normal neuronal iron homeostasis are surpassed, remain largely undetermined. How nigral neurons survive or succumb to iron-induced oxidative stress are relevant questions both to know about the etiology of the disease and to design neuroprotective strategies. In this work, we review the components of neural iron homeostasis and we summarize evidence from recent studies aimed to unravel the molecular basis of iron accumulation and dyshomeostasis in PD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aguirre P, Mena N, Tapia V, Arredondo M, Núñez MT (2005) Iron homeostasis in neuronal cells: a role for IREG1. BMC Neurosci 6: 1–3

    Article  CAS  Google Scholar 

  • Alam ZI, Jenner A, Daniel SE, et al. (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69: 1196–1203

    Article  PubMed  CAS  Google Scholar 

  • Anderson GJ, Frazer DM, McKie AT, Vulpe CD (2002) The ceruloplasmin homolog hephaestin and the control of intestinal iron absorption. Blood Cells Mol Dis 29: 367–375

    Article  PubMed  CAS  Google Scholar 

  • Arredondo M, Munñoz P, Mura CV, Núñez MT (2003) DMT1, a physiologically relevant apical Cu1+ transporter of intestinal cells. Am J Physiol Cell Physiol 284: 1525–1530

    Google Scholar 

  • Berg D, Grote C, Rausch WD, Maurer M, Wesemann W, Riederer P, Becker G (1999) Iron accumulation in the substantia nigra in rats visualized by ultrasound. Ultrasound Med Biol 25: 901–904

    Article  PubMed  CAS  Google Scholar 

  • Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC (1994) Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neurosci Lett 172: 151–154

    Article  PubMed  CAS  Google Scholar 

  • Bouton C, Hirling H, Drapier JC (1997) Redox modulation of iron regulatory proteins by peroxynitrite. J Biol Chem 272: 19969–19975

    Article  PubMed  CAS  Google Scholar 

  • Breuer W, Greenberg E, Cabantchik ZI (1997) Newly delivered transferring iron and oxidative cell injury. FEBS Lett 403: 213–219

    Article  PubMed  CAS  Google Scholar 

  • Connor JR, Boeshore KL, Benkovic SA, Menzies SL (1994) Isoforms of ferritin have a specific cellular distribution in the brain. J Neurosci Res 37: 461–465

    Article  PubMed  CAS  Google Scholar 

  • Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS (2002) Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 100: 695–697

    Article  PubMed  CAS  Google Scholar 

  • 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: 1830–1836

    Article  PubMed  CAS  Google Scholar 

  • Dexter DT, Sian J, Rose S, Hindmarsh JG, Mann VM, Cooper JM, Wells FR, Daniel SE, Lees AJ, Schapira AH, et al. (1994) Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann Neurol 35: 38–44

    Article  PubMed  CAS  Google Scholar 

  • Double KL, Gerlach M, Youdim MB, Riederer P (2000) Impaired iron homeostasis in Parkinson’s disease. J Neural Transm [Suppl 60]: 37–58

    Google Scholar 

  • Eisenstein RS, Ross KL (2003) Novel roles for iron regulatory proteins in the adaptive response to iron deficiency. J Nutr 133: 1510S–1516S

    PubMed  CAS  Google Scholar 

  • Epsztejn S, Kakhlon O, Glickstein H, Breuer W, Cabantchik I (1997) Fluorescence analysis of the labile iron pool of mammalian cells. Anal Biochem 248: 31–40

    Article  PubMed  CAS  Google Scholar 

  • 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 749:170–174

    Article  PubMed  CAS  Google Scholar 

  • Faucheux BA, Martin ME, Beaumont C, Hunot S, Hauw JJ, Agid Y, Hirsch EC (2002) Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson’s disease. J Neurochem 83: 320–330

    Article  PubMed  CAS  Google Scholar 

  • Floor E, Wetzel MG (1997) Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. J Neurochem 70: 268–275

    Article  Google Scholar 

  • Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 63: 793–807

    Article  PubMed  CAS  Google Scholar 

  • Good PF, Hsu A, Werner P, Perl DP, Olanow CW(1998) Protein nitration in Parkinson’s disease. J Neuropathol Exp Neurol 57: 338–342

    PubMed  CAS  Google Scholar 

  • Gorell JM, Ordidge RJ, Brown GG, Deniau JC, Buderer NM, Helpern JA (1995) Increased iron-related MRI contrast in the substantia nigra in Parkinson’s disease. Neurology 45: 1138–1143

    PubMed  CAS  Google Scholar 

  • Gotz ME, Double K, Gerlach M, Youdim MB, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann NY Acad Sci 1012: 193–208

    Article  PubMed  CAS  Google Scholar 

  • Grisoli M, Piperno A, Chiapparini L, Mariani R, Savoiardo M (2005) MR imaging of cerebral cortical involvement in aceruloplasminemia. Am J Neuroradiol 26: 657–661

    PubMed  Google Scholar 

  • Gunshin H, Mackenzie B, Berger UV, et al. (1997) Cloning and characterization of a proton-coupled mammalian metal ion transporter. Nature 388: 482–488

    Article  PubMed  CAS  Google Scholar 

  • Guo B, Phillips JD, Yu Y, Leibold EA (1995) Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem 270: 21645–21651

    Article  PubMed  CAS  Google Scholar 

  • Gutteridge JM, Halliwell B (2000) Free radicals and antioxidants in the year 2000. A historical look to the future. Ann NY Acad Sci 899: 136–147

    Article  PubMed  CAS  Google Scholar 

  • Hansen TM, Nielsen H, Bernth N, Moos T (1999) Expression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain. Brain Res Mol Brain Res 65: 186–197

    Article  PubMed  CAS  Google Scholar 

  • Hanson ES, Foot LM, Leibold EA (1999) Hypoxia post-translationally activates iron-regulatory protein 2. J Biol Chem 274: 5047–5052

    Article  PubMed  CAS  Google Scholar 

  • Hauptmann N, Cadenas E (1997) The oxygen paradox: Biochemistry of active oxygen. In: Scandalios JG (ed) Oxidative stress and the molecular biology of antioxidant defenses. Cold Spring Harbor Laboratory Press, New York, pp 1–20

    Google Scholar 

  • He Y, Thong PS, Lee T, Leong SK, Mao BY, Dong F, Watt F (2003) Dopaminergic cell death precedes iron elevation in MPTP-injected monkeys. Free Radic Biol Med 35: 540–547

    Article  PubMed  CAS  Google Scholar 

  • Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Annu Rev Nutr 22: 439–458

    Article  PubMed  CAS  Google Scholar 

  • Henze C, Earl C, Sautter J, Schmidt N, Themann C, Hartmann A, Oertel WH (2005) Reactive oxidative and nitrogen species in the nigrostriatal system following striatal 6-hydroxydopamine lesion in rats. Brain Res 1052: 97–104

    Article  PubMed  CAS  Google Scholar 

  • Hill JM, Ruff MR, Weber RJ, Pert CB (1985) Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution. Proc Natl Acad Sci USA 82: 4553–4557

    Article  PubMed  CAS  Google Scholar 

  • 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: 446–451

    Article  PubMed  CAS  Google Scholar 

  • Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann NY Acad Sci 991: 214–228

    Article  PubMed  CAS  Google Scholar 

  • Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA 99: 12345–12350

    Article  PubMed  CAS  Google Scholar 

  • Hunot S, Brugg B, Ricard D, Michel PP, Muriel MP, Ruberg M, Faucheux BA, Agid Y, Hirsch EC (1997) Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with Parkinson disease. Proc Natl Acad Sci USA 94: 7531–7536

    Article  PubMed  CAS  Google Scholar 

  • Kakhlon O, Cabantchik ZI (2002) The labile iron pool: characterization, measurement, and participation in cellular processes. Free Radic Biol Med 33: 1037–1046

    Article  PubMed  CAS  Google Scholar 

  • 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: 899–909

    Article  PubMed  CAS  Google Scholar 

  • Kim S, Ponka P (2002) Nitrogen monoxide-mediated control of ferritin synthesis: implications for macrophage iron homeostasis. Proc Natl Acad Sci USA 99: 12214–12219

    Article  PubMed  CAS  Google Scholar 

  • Kruszewski M (2003) Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res 531: 81–92

    PubMed  CAS  Google Scholar 

  • Latunde-Dada GO, Vulpe CD, Anderson GJ, Simpson RJ, McKie AT (2004) Tissue-specific changes in iron metabolism genes in mice following phenylhydrazine-induced haemolysis. Biochim Biophys Acta 690: 169–176

    Google Scholar 

  • Ludwiczek S, Aigner E, Theurl I, Weiss G (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101: 4148–4154

    Article  PubMed  CAS  Google Scholar 

  • Martins EA, Robalinho RL, Meneghini R (1995) Oxidative stress induces activation of a cytosolic protein responsible for control of iron uptake. Arch Biochem Biophys 10: 128–134

    Article  Google Scholar 

  • 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: 299–309

    Article  PubMed  CAS  Google Scholar 

  • McKie AT, Barrow D, Latunde-Dada GO, et al. (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291: 1755–1759

    Article  PubMed  CAS  Google Scholar 

  • McNaught KS, Olanow CW(2005) Protein aggregation in the pathogenesis of familial and sporadic Parkinson’s disease. Neurobiol: Epub ahead of print

    Google Scholar 

  • Mehlhase J, Sandig G, Pantopoulos K, Grune T (2005) Oxidation-induced ferritin turnover in microglial cells: role of proteasome. Free Radic Biol Med 38: 276–285

    Article  PubMed  CAS  Google Scholar 

  • Miyajima H, Takahashi Y, Kono S (2003) Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals 16: 205–213

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, Togari A, Tanaka K, Ogawa N, Ichinose H, Nagatsu T (1999) Increase in level of tumor necrosis factor (TNF)-alpha in 6-hydroxydopamine-lesioned striatum in rats without influence of systemic L-DOPA on the TNF-alpha induction. Neurosci Lett 268: 101–104

    Article  PubMed  CAS  Google Scholar 

  • Nanami M, Ookawara T, Otaki Y, Ito K, Moriguchi R, Miyagawa K, Hasuike Y, Izumi M, Eguchi H, Suzuki K, Nakanishi T (2005) Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells. Arterioscler Thromb Vasc Biol 25: 2495–2501

    Article  PubMed  CAS  Google Scholar 

  • Núñez MT, Gaete V, Watkins JA, Glass J (1990) Mobilization of iron from endocytic vesicles: the effect of acidification and reduction. J Biol Chem 265: 6688–6692

    PubMed  Google Scholar 

  • Núñez MT, Gallardo V, Múñoz P, Tapia V, Esparza A, Salazar J, Speisky H (2004) Progressive iron accumulation induces a biphasic change in the glutathione content of neuroblastoma cells. Free Radic Biol Med 37: 953–960

    Article  PubMed  CAS  Google Scholar 

  • Núñez-Millacura C, Tapia V, Múñoz P, Maccioni RB, Núñez MT (2002) An oxidative stress-mediated positive-feedback iron uptake loop in neuronal cells. J Neurochem 82: 240–248

    Article  PubMed  Google Scholar 

  • Paradkar PN, Roth JA (2005) Post-translational and transcriptional regulation of DMT1 during P19 embryonic carcinoma cell differentiation by retinoic acid. Biochem J: Epub ahead of print

    Google Scholar 

  • Patel BN, David S (1997) A novel glycophosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 272: 20185–20190

    Article  PubMed  CAS  Google Scholar 

  • Perry G, Taddeo MA, Petersen RB, Castellani RJ, Harris PLR, Siedlak SL, Cash AD, Liu Q, Nunomura A, Atwood CS, Smith MA (2003) Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease. Biometals 16: 77–81

    Article  PubMed  CAS  Google Scholar 

  • Petrat F, de Groot H, Sustmann R, Rauen U (2002) The chelatable iron pool in living cells: a methodically defined quantity. Biol Chem 383: 489–502

    Article  PubMed  CAS  Google Scholar 

  • Reiber H, Ruff M, Uhr M (1993) Ascorbate concentration in human cerebrospinal fluid (CSF) and serum. Intrathecal accumulation and CSF flow rate. Clin Chim Acta 217: 163–173

    Article  PubMed  CAS  Google Scholar 

  • 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: 515–520

    Article  PubMed  CAS  Google Scholar 

  • Sayre LM, Perry G, Atwood CS, Smith MA (2000) The role of metals in neurodegenerative diseases. Cell Mol Biol 46: 731–741

    PubMed  CAS  Google Scholar 

  • Schalinske KL, Eisenstein RS (1996) Phosphorylation and activation of both iron regulatory proteins 1 and 2 in HL-60 cells. J Biol Chem 271: 7168–7176

    Article  PubMed  CAS  Google Scholar 

  • Shoham S, Youdim MB (2002) The effects of iron deficiency and iron and zinc supplementation on rat hippocampus ferritin. J Neural Transm 109: 1241–1256

    Article  PubMed  CAS  Google Scholar 

  • 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: 199–205

    Article  PubMed  CAS  Google Scholar 

  • Symons MCR, Gutteridge JMC eds (1998) Free radicals and iron: chemistry, biology and medicine. Oxford University Press, New York

    Google Scholar 

  • Wang X, Garrick MD, Yang F, Dailey LA, Piantadosi CA, Ghio AJ (2005) TNF, IFN-gamma, and endotoxin increase expression of DMT1 in bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 289:L24–L33

    Article  PubMed  CAS  Google Scholar 

  • Williams J, Moreton K (1980) The distribution of iron between the metalbinding sites of transferrin human serum. Biochem J 185: 483–488

    PubMed  CAS  Google Scholar 

  • 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: 108–117

    Article  PubMed  CAS  Google Scholar 

  • Yang F, Haile DJ, Wang X, Dailey LA, Stonehuerner JG, Ghio AJ (2005) Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung. Am J Physiol Lung Cell Mol Physiol 289: L14–L23

    Article  PubMed  CAS  Google Scholar 

  • Youdim MB, Riederer P (1993) The role of iron in senescence of dopaminergic neurons in Parkinson’s disease. J Neural Transm [Suppl 40]: 57–67

    Google Scholar 

  • Youdim MB, Stephenson G, Ben Shachar D (2004) 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

    Article  PubMed  CAS  Google Scholar 

  • Youdim MB, Fridkin M, Zheng H (2005) Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech Ageing Dev 126: 317–326

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, and Cell Dynamic and Biotechnology Research Center, Faculty of Sciences, University of Chile, Santiago, Chile

    J. Salazar, N. Mena & Dr. M. T. Núñez

  2. INSERM U679, Hopital de la Salpetriere, Paris, France

    J. Salazar

  3. Department of Biology, Faculty of Sciences, University of Chile, Las Palmeras 3425, Ñuñoa, Santiago, Chile

    Dr. M. T. Núñez

Authors
  1. J. Salazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Mena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dr. M. T. Núñez
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute Alfred Fessard de Neurosciences, CNRS, Gif Yvette, France

    H. Parvez

  2. Klinik und Poliklinik für Psychiatrie und Psychotherapie, Würzburg, Germany

    P. Riederer

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer-Verlag

About this chapter

Cite this chapter

Salazar, J., Mena, N., Núñez, M.T. (2006). Iron dyshomeostasis in Parkinson’s disease. In: Parvez, H., Riederer, P. (eds) Oxidative Stress and Neuroprotection. Journal of Neural Transmission. Supplementa, vol 71. Springer, Vienna. https://doi.org/10.1007/978-3-211-33328-0_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-211-33328-0_22

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-211-33327-3

  • Online ISBN: 978-3-211-33328-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation