Advertisement

Neurotoxicity Research

, Volume 25, Issue 1, pp 13–23 | Cite as

Neuromelanin of the Human Substantia Nigra: An Update

  • Fabio A. Zucca
  • Emy Basso
  • Francesca A. Cupaioli
  • Emanuele Ferrari
  • David Sulzer
  • Luigi Casella
  • Luigi ZeccaEmail author
Review Article

Abstract

Dopaminergic neurons of the substantia nigra selectively degenerate over the course of Parkinson’s disease. These neurons are also the most heavily pigmented cells of the brain, accumulating the dark pigment neuromelanin over a lifetime. The massive presence of neuromelanin in these brain areas has long been suspected as a key factor involved in the selective vulnerability of neurons. The high concentration of neuromelanin in substantia nigra neurons seems to be linked to the presence of considerable amounts of cytosolic dopamine that have not been sequestered into synaptic vesicles. Over the past few years, studies have uncovered a dual nature of neuromelanin. Intraneuronal neuromelanin can be a protective factor, shielding the cells from toxic effects of redox active metals, toxins, and excess of cytosolic catecholamines. In contrast, neuromelanin released by dying neurons can contribute to the activation of neuroglia triggering the neuroinflammation that characterizes Parkinson’s disease. This article reviews recent studies on the molecular aspects of neuromelanin of the human substantia nigra.

Keywords

Neuromelanin Substantia nigra Parkinson’s disease Aging Neuroinflammation Neurodegeneration 

Notes

Acknowledgments

EB, FAC, EF, LZ, and FAZ were supported by Italian Ministry of Education, University, and Research (MIUR)–National Research Programme (PNR)–CNR Flagship “InterOmics” Project (PB.P05), by PNR–CNR Aging program 2012–2014 and by MIUR–Medical Research in Italy (MERIT) Project RBNE08ZZN7. DS’s effort is supported by the Udall Center of Excellence in Parkinson’s disease, and the Parkinson’s disease and JPB Foundations. LC and LZ also acknowledge the MIUR–Research Projects of National Interest (PRIN) 2012–2011 prot. 2010M2JARJ.

Conflict of interest

All authors declare no conflicts of interest.

References

  1. Aime S, Bergamasco B, Biglino D, Digilio G, Fasano M, Giamello E, Lopiano L (1997) EPR investigations of the iron domain in neuromelanin. Biochim Biophys Acta 1361:49–58PubMedGoogle Scholar
  2. Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 13:221–227PubMedGoogle Scholar
  3. Barden H (1970) Relationship of golgi thiaminepyrophosphatase and lysosomal acid phosphatase to neuromelanin and lipofuscin in cerebral neurons of the aging rhesus monkey. J Neuropathol Exp Neurol 29:225–240PubMedGoogle Scholar
  4. Barden H (1971) The histochemical distribution and localization of copper, iron, neuromelanin and lysosomal enzyme activity in the brain of aging rhesus monkey and the dog. J Neuropathol Exp Neurol 30:650–667PubMedGoogle Scholar
  5. Bazelon M, Fenichel GM, Randall J (1967) Studies on neuromelanin. I. A melanin system in the human adult brainstem. Neurology 17:512–519PubMedGoogle Scholar
  6. Beach TG, Sue LI, Walker DG, Lue LF, Connor DJ, Caviness JN, Sabbagh MN, Adler CH (2007) Marked microglial reaction in normal aging human substantia nigra: correlation with extraneuronal neuromelanin pigment deposits. Acta Neuropathol 114:419–424PubMedGoogle Scholar
  7. Bogerts B (1981) A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker. J Comp Neurol 197:63–80PubMedGoogle Scholar
  8. Bohic S, Murphy K, Paulus W, Cloetens P, Salomé M, Susini J, Double K (2008) Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy. Anal Chem 80:9557–9566PubMedGoogle Scholar
  9. Bridelli MG, Tampellini D, Zecca L (1999) The structure of neuromelanin and its iron binding site studied by infrared spectroscopy. FEBS Lett 457:18–22PubMedGoogle Scholar
  10. Bush WD, Garguilo J, Zucca FA, Albertini A, Zecca L, Edwards GS, Nemanich RJ, Simon JD (2006) The surface oxidation potential of human neuromelanin reveals a spherical architecture with a pheomelanin core and a eumelanin surface. Proc Natl Acad Sci USA 103:14785–14789PubMedGoogle Scholar
  11. Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B (2002) Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol Appl Neurobiol 28:283–291PubMedGoogle Scholar
  12. Coon S, Stark A, Peterson E, Gloi A, Kortsha G, Pounds J, Chettle D, Gorell J (2006) Whole-body lifetime occupational lead exposure and risk of Parkinson’s disease. Environ Health Perspect 114:1872–1876PubMedCentralPubMedGoogle Scholar
  13. Cowen D (1986) The melanoneurons of the human cerebellum (nucleus pigmentosus cerebellaris) and homologues in the monkey. J Neuropathol Exp Neurol 45:205–221PubMedGoogle Scholar
  14. Crippa R, Wang QJ, Eisner M, Moss SC, Zecca L, Zschack P, Gog T (1996) Structure of human neuromelanin by X-ray diffraction: comparison with synthetics. Abstract. XVIth Internat Pigment Cell Conference, Anaheim. Pigment Cell Res S5:2Google Scholar
  15. D’Amato RJ, Lipman ZP, Snyder SH (1986) Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+binds to neuromelanin. Science 231:987–989PubMedGoogle Scholar
  16. DeMattei M, Levi AC, Fariello RG (1986) Neuromelanic pigment in substantia nigra neurons of rats and dogs. Neurosci Lett 72:37–42PubMedGoogle Scholar
  17. Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, Marsden CD (1987) Increased nigral iron content in postmortem parkinsonian brain. Lancet 2:1219–1220PubMedGoogle Scholar
  18. 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 52:1830–1836PubMedGoogle Scholar
  19. Double KL, Zecca L, Costi P, Mauer M, Griesinger C, Ito S, Ben-Shachar D, Bringmann G, Fariello RG, Riederer P, Gerlach M (2000) Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins. J Neurochem 75:2583–2589PubMedGoogle Scholar
  20. Double KL, Ben-Shachar D, Youdim MB, Zecca L, Riederer P, Gerlach M (2002) Influence of neuromelanin on oxidative pathways within the human substantia nigra. Neurotoxicol Teratol 24:621–628PubMedGoogle Scholar
  21. Double KL, Gerlach M, Schünemann 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 66:489–494PubMedGoogle Scholar
  22. Duffy P, Tennyson VM (1965) Phase and electron microscopic observations of Lewy bodies and melanin granules in the substantia nigra and locus coeruleus in Parkinson’s disease. J Neuropathol Exp Neurol 24:398–414Google Scholar
  23. Earle KM (1968) Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1–14PubMedGoogle Scholar
  24. Engelen M, Vanna R, Bellei C, Zucca FA, Wakamatsu K, Monzani E, Ito S, Casella L, Zecca L (2012) Neuromelanins of human brain have soluble and insoluble components with dolichols attached to the melanic structure. PLoS One 7:e48490PubMedCentralPubMedGoogle Scholar
  25. Enochs WS, Sarna T, Zecca L, Riley PA, Swartz HM (1994) The roles of neuromelanin, binding of metal ions, and oxidative cytotoxicity in the pathogenesis of Parkinson’s disease: a hypothesis. J Neural Transm Park Dis Dement Sect 7:83–100PubMedGoogle Scholar
  26. Enochs WS, Petherick P, Bogdanova A, Mohr U, Weissleder R (1997) Paramagnetic metal scavenging by melanin: MR imaging. Radiology 204:417–423PubMedGoogle Scholar
  27. Fasano M, Bergamasco B, Lopiano L (2006) Modifications of the iron-neuromelanin system in Parkinson’s disease. J Neurochem 96:909–916PubMedGoogle Scholar
  28. Faucheux BA, Martin ME, Beaumont C, Hauw JJ, Agid Y, Hirsch EC (2003) Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson’s disease. J Neurochem 86:1142–1148PubMedGoogle Scholar
  29. Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301PubMedGoogle Scholar
  30. Fedorow H, Pickford R, Hook JM, Double KL, Halliday GM, Gerlach M, Riederer P, Garner B (2005) Dolichol is the major lipid component of human substantia nigra neuromelanin. J Neurochem 92:990–995PubMedGoogle Scholar
  31. Fedorow H, Pickford R, Kettle E, Cartwright M, Halliday GM, Gerlach M, Riederer P, Garner B, Double KL (2006) Investigation of the lipid component of neuromelanin. J Neural Transm 113:735–739PubMedGoogle Scholar
  32. Fellman JH (1958) Epinephrine metabolites and pigmentation in the central nervous system in a case of phenylpyruvic oligophrenia. J Neurol Neurosurg Psychiatry 21:58–62PubMedGoogle Scholar
  33. Fenichel GM, Bazelon M (1968) Studies on neuromelanin. II. Melanin in the brainstems of infants and children. Neurology 18:817–820PubMedGoogle Scholar
  34. Ferrari E, Engelen M, Monzani E, Sturini M, Girotto S, Bubacco L, Zecca L, Casella L (2013) Synthesis and structural characterization of soluble neuromelanin analogs provides important clues to its biosynthesis. J Biol Inorg Chem 18:81–93PubMedGoogle Scholar
  35. Foley JM, Baxter D (1958) On the nature of pigment granules in the cells of the locus coeruleus and substantia nigra. J Neuropathol Exp Neurol 17:586–598PubMedGoogle Scholar
  36. Foppoli C, Coccia R, Cini C, Rosei MA (1997) Catecholamines oxidation by xanthine oxidase. Biochim Biophys Acta 1334:200–206PubMedGoogle Scholar
  37. Fornstedt B, Rosengren E, Carlsson A (1986) Occurrence and distribution of 5-S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eight mammalian species. Neuropharmacology 25:451–454PubMedGoogle Scholar
  38. Galzigna L, De Iuliis A, Zanatta L (2000) Enzymatic dopamine peroxidation in substantia nigra of human brain. Clin Chim Acta 300:131–138PubMedGoogle Scholar
  39. Gerlach M, Trautwein AX, Zecca L, Youdim MB, Riederer P (1995) Mössbauer spectroscopic studies of purified human neuromelanin isolated from the substantia nigra. J Neurochem 65:923–926PubMedGoogle Scholar
  40. Gibb WR (1992) Melanin, tyrosine hydroxylase, calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson’s disease. Brain Res 581:283–291PubMedGoogle Scholar
  41. Gibb WR, Lees AJ (1991) Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 54:388–396PubMedGoogle Scholar
  42. 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 593:343–346PubMedGoogle Scholar
  43. 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 20:239–247PubMedGoogle Scholar
  44. Graham DG (1979) On the origin and significance of neuromelanin. Arch Pathol Lab Med 103:359–362PubMedGoogle Scholar
  45. Greggio E, Bergantino E, Carter D, Ahmad R, Costin GE, Hearing VJ, Clarimon J, Singleton A, Eerola J, Hellström O, Tienari PJ, Miller DW, Beilina A, Bubacco L, Cookson MR (2005) Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson’s disease. J Neurochem 93:246–256PubMedGoogle Scholar
  46. Haavik J (1997) L-DOPA is a substrate for tyrosine hydroxylase. J Neurochem 69:1720–1728PubMedGoogle Scholar
  47. Halliday GM, Fedorow H, Rickert CH, Gerlach M, Riederer P, Double KL (2006) Evidence for specific phases in the development of human neuromelanin. J Neural Transm 113:721–728PubMedGoogle Scholar
  48. Hastings TG (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 64:919–924PubMedGoogle Scholar
  49. Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348PubMedGoogle Scholar
  50. Ikemoto K, Nagatsu I, Ito S, King RA, Nishimura A, Nagatsu T (1998) Does tyrosinase exist in neuromelanin-pigmented neurons in the human substantia nigra? Neurosci Lett 253:198–200PubMedGoogle Scholar
  51. Ito S (2006) Encapsulation of a reactive core in neuromelanin. Proc Natl Acad Sci USA 103:14647–14648PubMedGoogle Scholar
  52. Ito S, Wakamatsu K (2008) Chemistry of mixed melanogenesis–pivotal roles of dopaquinone. Photochem Photobiol 84:582–592PubMedGoogle Scholar
  53. 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 59:1168–1171PubMedGoogle Scholar
  54. Karlsson O, Lindquist NG (2013) Melanin affinity and its possible role in neurodegeneration. J Neural Transm [Epub ahead of print]Google Scholar
  55. Karlsson O, Berg C, Brittebo EB, Lindquist NG (2009) Retention of the cyanobacterial neurotoxin β-N-methylamino-l-alanine in melanin and neuromelanin-containing cells—a possible link between Parkinson–dementia complex and pigmentary retinopathy. Pigment Cell Melanoma Res 22:120–130PubMedGoogle Scholar
  56. Kastner A, Hirsch EC, Lejeune O, Javoy-Agid F, Rascol O, Agid Y (1992) Is the vulnerability of neurons in the substantia nigra of patients with Parkinson’s disease related to their neuromelanin content? J Neurochem 59:1080–1109PubMedGoogle Scholar
  57. Kemali M, Gioffré D (1985) Anatomical localisation of neuromelanin in the brains of the frog and tadpole. Ultrastructural comparison of neuromelanin with other melanins. J Anat 142:73–83PubMedGoogle Scholar
  58. Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20:6309–6316PubMedGoogle Scholar
  59. Kropf AJ, Bunker BA, Eisner M, Moss SC, Zecca L, Stroppolo A, Crippa PR (1998) X-ray absorption fine-structure spectroscopy studies of Fe sites in natural human neuromelanin and synthetic analogues. Biophys J 75:3135–3142PubMedCentralPubMedGoogle Scholar
  60. Kubis N, Faucheux BA, Ransmayr G, Damier P, Duyckaerts C, Henin D, Forette B, Le Charpentier Y, Hauw JJ, Agid Y, Hirsch EC (2000) Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain 123:366–373PubMedGoogle Scholar
  61. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605PubMedGoogle Scholar
  62. Larsson BS (1993) Interaction between chemicals and melanin. Pigment Cell Res 6:127–133PubMedGoogle Scholar
  63. Liang CL, Nelson O, Yazdani U, Pasbakhsh P, German DC (2004) Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J Comp Neurol 473:97–106PubMedGoogle Scholar
  64. Lindquist NG, Larsson BS, Lydén-Sokolowski A (1987) Neuromelanin and its possible protective and destructive properties. Pigment Cell Res 1:133–136PubMedGoogle Scholar
  65. Lindquist NG, Larsson BS, Lyden-Sokolowski A (1988) Autoradiography of [14C]paraquat or [14C]diquat in frogs and mice: accumulation in neuromelanin. Neurosci Lett 93:1–6PubMedGoogle Scholar
  66. Liu Y, Edwards RH (1997) The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci 20:125–156PubMedGoogle Scholar
  67. Ma SY, Röytt M, Collan Y, Rinne JO (1999) Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 25:394–399PubMedGoogle Scholar
  68. Makin OS, Serpell LC (2005) Structures for amyloid fibrils. FEBS J 272:5950–5961PubMedGoogle Scholar
  69. Mann DM, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 21:193–203PubMedGoogle Scholar
  70. Marsden CD (1961) Pigmentation in the nucleus substantiae nigrae of mammals. J Anat 95:256–261PubMedGoogle Scholar
  71. Marsden CD (1983) Neuromelanin and Parkinson’s disease. J Neural Transm Suppl 19:121–141PubMedGoogle Scholar
  72. Mattammal MB, Strong R, Lakshmi VM, Chung HD, Stephenson AH (1995) Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson’s disease. J Neurochem 64:1645–1654PubMedGoogle Scholar
  73. Matzuk MM, Saper CB (1985) Preservation of hypothalamic dopaminergic neurons in Parkinson’s disease. Ann Neurol 18:552–555PubMedGoogle Scholar
  74. McGeer PL, McGeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34:33–35PubMedGoogle Scholar
  75. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291PubMedGoogle Scholar
  76. Meredith P, Sarna T (2006) The physical and chemical properties of eumelanin. Pigment Cell Res 19:572–594PubMedGoogle Scholar
  77. Muthane U, Yasha TC, Shankar SK (1998) Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India. Ann Neurol 43:283–287PubMedGoogle Scholar
  78. Naoi M, Yi H, Maruyama W, Inaba K, Shamoto-Nagai M, Akao Y, Gerlach M, Riederer P (2009) Glutathione redox status in mitochondria and cytoplasm differentially and sequentially activates apoptosis cascade in dopamine-melanin-treated SH-SY5Y cells. Neurosci Lett 465:118–122PubMedGoogle Scholar
  79. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36:2503–2508PubMedGoogle Scholar
  80. Nicolis S, Zucchelli M, Monzani E, Casella L (2008) Myoglobin modification by enzyme-generated dopamine reactive species. Chem Eur J 14:8661–8673PubMedGoogle Scholar
  81. Oberländer U, Pletinckx K, Döhler A, Müller N, Lutz MB, Arzberger T, Riederer P, Gerlach M, Koutsilieri E, Scheller C (2011) Neuromelanin is an immune stimulator for dendritic cells in vitro. BMC Neurosci 12:116PubMedCentralPubMedGoogle Scholar
  82. Ohtsuka C, Sasaki M, Konno K, Koide M, Kato K, Takahashi J, Takahashi S, Kudo K, Yamashita F, Terayama Y (2013) Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson’s disease using neuromelanin-sensitive MR imaging. Neurosci Lett 541:93–98PubMedGoogle Scholar
  83. Okun MR (1997) The role of peroxidase in neuromelanin synthesis: a review. Physiol Chem Phys Med NMR 29:15–22PubMedGoogle Scholar
  84. Östergren A, Annas A, Skog K, Lindquist NG, Brittebo EB (2004) Long-term retention of neurotoxic beta-carbolines in brain neuromelanin. J Neural Transm 111:141–157PubMedGoogle Scholar
  85. Pakkenberg B, Møller A, Gundersen HJ, Mouritzen Dam A, Pakkenberg H (1991) The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry 54:30–33PubMedGoogle Scholar
  86. Rabey JM, Hefti F (1990) Neuromelanin synthesis in rat and human substantia nigra. J Neural Transm Park Dis Dement Sect. 2:1–14PubMedGoogle Scholar
  87. Salazar M, Sokoloski TD, Patil PN (1978) Binding of dopaminergic drugs by the neuromelanin of the substantia nigra, synthetic melanins and melanin granules. Fed Proc 37:2403–2407PubMedGoogle Scholar
  88. Sarna T, Korytowsky W, Zareba M, Zecca L (1993) Structure and chemical reactivity of metal-ion complexes with neuromelanin. XVth International Pigment Cell Conference, London. Pigment Cell Res 6:287Google Scholar
  89. Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, Takahashi S, Ehara S, Terayama Y, Sakai A (2006) Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson’s disease. Neuroreport 17:1215–1218PubMedGoogle Scholar
  90. Schwarz ST, Rittman T, Gontu V, Morgan PS, Bajaj N, Auer DP (2011) T1-weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson’s disease. Mov Disord 26:1633–1638PubMedGoogle Scholar
  91. Shamoto-Nagai M, Maruyama W, Akao Y, Osawa T, Tribl F, Gerlach M, Zucca FA, Zecca L, Riederer P, Naoi M (2004) Neuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells. J Neural Transm 111:1253–1265PubMedGoogle Scholar
  92. Shamoto-Nagai M, Maruyama W, Yi H, Akao Y, Tribl F, Gerlach M, Osawa T, Riederer P, Naoi M (2006) Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome. J Neural Transm 113:633–644PubMedGoogle Scholar
  93. Shima T, Sarna T, Swartz HM, Stroppolo A, Gerbasi R, Zecca L (1997) Binding of iron to neuromelanin of human substantia nigra and synthetic melanin: an electron paramagnetic resonance spectroscopy study. Free Radic Biol Med 23:110–119PubMedGoogle Scholar
  94. Simuni T, Hurtig H (2002) A continuing controversy: is levodopa toxic? chap 32, In: Factor SA, Weiner WJ (eds) Parkinson’s disease: diagnosis and clinical management. Demos Medical Publishing, New YorkGoogle Scholar
  95. 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 74:199–205PubMedGoogle Scholar
  96. Sulzer D, Zecca L (2000) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1:181–195PubMedGoogle Scholar
  97. Sulzer D, Bogulavsky J, Larsen KE, Behr G, Karatekin E, Kleinman MH, Turro N, Krantz D, Edwards RH, Greene LA, Zecca L (2000) Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci USA 97:11869–11874PubMedGoogle Scholar
  98. Sulzer D, Mosharov E, Talloczy Z, Zucca FA, Simon JD, Zecca L (2008) Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease. J Neurochem 106:24–36PubMedGoogle Scholar
  99. Swartz HM, Sarna T, Zecca L (1992) Modulation by neuromelanin of the availability and reactivity of metal ions. Ann Neurol 32:S69–S75PubMedGoogle Scholar
  100. Tawara T, Fukushima T, Hojo N, Isobe A, Shiwaku K, Setogawa T, Yamane Y (1996) Effects of paraquat on mitochondrial electron transport system and catecholamine contents in rat brain. Arch Toxicol 70:585–589PubMedGoogle Scholar
  101. Tousi NS, Buck DJ, Zecca L, Davis RL (2010) Neuromelanin inhibits CXCL10 expression in human astroglial cells. Neurosci Lett 486:47–50PubMedCentralPubMedGoogle Scholar
  102. Tribl F, Gerlach M, Marcus K, Asan E, Tatschner T, Arzberger T, Meyer HE, Bringmann G, Riederer P (2005) “Subcellular proteomics” of neuromelanin granules isolated from the human brain. Mol Cell Proteomics 4:945–957PubMedGoogle Scholar
  103. Tribl F, Arzberger T, Riederer P, Gerlach M (2007) Tyrosinase is not detected in human catecholaminergic neurons by immunohistochemistry and western blot analysis. J Neural Transm Suppl 72:51–55PubMedGoogle Scholar
  104. Van Woert MH, Prasad KN, Borg DC (1967) Spectroscopic studies of substantia nigra pigment in human subjects. J Neurochem 14:707–716PubMedGoogle Scholar
  105. Venkateshappa C, Harish G, Mythri RB, Mahadevan A, Bharath MM, Shankar SK (2012) Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson’s disease. Neurochem Res 37:358–369PubMedGoogle Scholar
  106. Wakamatsu K, Ito S (2002) Advanced chemical methods in melanin determination. Pigment Cell Res 15:174–183PubMedGoogle Scholar
  107. Wakamatsu K, Fujikawa K, Zucca FA, Zecca L, Ito S (2003) The structure of neuromelanin as studied by chemical degradative methods. J Neurochem 86:1015–1023PubMedGoogle Scholar
  108. Wakamatsu K, Murase T, Zucca FA, Zecca L, Ito S (2012) Biosynthetic pathway to neuromelanin and its aging process. Pigment Cell Melanoma Res 25:792–803PubMedGoogle Scholar
  109. Ward WC, Guan Z, Zucca FA, Fariello RG, Kordestani R, Zecca L, Raetz CR, Simon JD (2007) Identification and quantification of dolichol and dolichoic acid in neuromelanin from substantia nigra of the human brain. J Lipid Res 48:1457–1462PubMedGoogle Scholar
  110. Wilms H, Rosenstiel P, Sievers J, Deuschl G, Zecca L, Lucius R (2003) Activation of microglia by human neuromelanin is NF-kappaB dependent and involves p38 mitogen-activated protein kinase: implications for Parkinson’s disease. FASEB J 17:500–502PubMedGoogle Scholar
  111. Xu Y, Stokes AH, Freeman WM, Kumer SC, Vogt BA, Vrana KE (1997) Tyrosinase mRNA is expressed in human substantia nigra. Brain Res Mol Brain Res 45:159–162PubMedGoogle Scholar
  112. Yamamoto T, Anno M, Sato T (1987) Effects of paraquat on mitochondria of rat skeletal muscle. Comp Biochem Physiol C 86:375–378PubMedGoogle Scholar
  113. Youdim MB, Ben-Shachar D, Riederer P (1989) Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand Suppl 126:47–54PubMedGoogle Scholar
  114. Zareba M, Bober A, Korytowski W, Zecca L, Sarna T (1995) The effect of a synthetic neuromelanin on yield of free hydroxyl radicals generated in model systems. Biochim Biophys Acta 1271:343–348PubMedGoogle Scholar
  115. Zecca L, Pietra R, Goj C, Mecacci C, Radice D, Sabbioni E (1994) Iron and other metals in neuromelanin, substantia nigra, and putamen of human brain. J Neurochem 62:1097–1101PubMedGoogle Scholar
  116. Zecca L, Shima T, Stroppolo A, Goj C, Battiston GA, Gerbasi R, Sarna T, Swartz HM (1996) Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience 73:407–415PubMedGoogle Scholar
  117. Zecca L, Costi P, Mecacci C, Ito S, Terreni M, Sonnino S (2000) Interaction of human substantia nigra neuromelanin with lipids and peptides. J Neurochem 74:1758–1765PubMedGoogle Scholar
  118. Zecca L, Tampellini D, Costi P, Rizzio E, Giaveri G, Gallorini M (2001a) Combined biochemical separation and INAA for the determination of iron and other metals in Neuromelanin of human brain Substantia Nigra. J Radioanal Nucl Chem 249:449–454Google Scholar
  119. Zecca L, Gallorini M, Schünemann V, Trautwein AX, Gerlach M, Riederer P, Vezzoni P, Tampellini D (2001b) Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J Neurochem 76:1766–1773PubMedGoogle Scholar
  120. Zecca L, Fariello R, Riederer P, Sulzer D, Gatti A, Tampellini D (2002) The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson’s disease. FEBS Lett 510:216–220PubMedGoogle Scholar
  121. 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 USA 101:9843–9984PubMedGoogle Scholar
  122. Zecca L, Bellei C, Costi P, Albertini A, Monzani E, Casella L, Gallorini M, Bergamaschi L, Moscatelli A, Turro NJ, Eisner M, Crippa PR, Ito S, Wakamatsu K, Bush WD, Ward WC, Simon JD, Zucca FA (2008a) New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. Proc Natl Acad Sci USA 105:17567–17572PubMedGoogle Scholar
  123. Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T (2008b) Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J Neurochem 106:1866–1875PubMedGoogle Scholar
  124. Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J, Lucius R (2008c) Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson’s disease. Acta Neuropathol 116:47–55PubMedGoogle Scholar
  125. Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, Faust R, Qian SY, Miller DS, Chignell CF, Wilson B, Jackson-Lewis V, Przedborski S, Joset D, Loike J, Hong JS, Sulzer D, Zecca L (2011) Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res 19:63–72PubMedCentralPubMedGoogle Scholar
  126. Zhang W, Zecca L, Wilson B, Ren HW, Wang YJ, Wang XM, Hong JS (2013) Human neuromelanin: an endogenous microglial activator for dopaminergic neuron death. Front Biosci (Elite Ed) 1:1–11Google Scholar
  127. Zucca FA, Bellei C, Giannelli S, Terreni MR, Gallorini M, Rizzio E, Pezzoli G, Albertini A, Zecca L (2006) Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: consequences for neuronal vulnerability. J Neural Transm 113:757–767PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Fabio A. Zucca
    • 1
  • Emy Basso
    • 1
  • Francesca A. Cupaioli
    • 1
  • Emanuele Ferrari
    • 1
  • David Sulzer
    • 3
  • Luigi Casella
    • 2
  • Luigi Zecca
    • 1
    Email author
  1. 1.Institute of Biomedical TechnologiesNational Research Council of ItalySegrate (MI)Italy
  2. 2.Department of ChemistryUniversity of PaviaPaviaItaly
  3. 3.Department of Psychiatry, Neurology and PharmacologyColumbia UniversityNew YorkUSA

Personalised recommendations