Skip to main content
SpringerLink
Log in

Neuromelanin of the Human Substantia Nigra: An Update

  • Review Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

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.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • 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 1361:49–58

    CAS  PubMed  Google Scholar 

  • Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 13:221–227

    CAS  PubMed  Google Scholar 

  • 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 29:225–240

    CAS  PubMed  Google Scholar 

  • 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 30:650–667

    CAS  PubMed  Google Scholar 

  • Bazelon M, Fenichel GM, Randall J (1967) Studies on neuromelanin. I. A melanin system in the human adult brainstem. Neurology 17:512–519

    CAS  PubMed  Google Scholar 

  • 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 114:419–424

    PubMed  Google Scholar 

  • Bogerts B (1981) A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker. J Comp Neurol 197:63–80

    CAS  PubMed  Google Scholar 

  • 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 80:9557–9566

    CAS  PubMed  Google Scholar 

  • Bridelli MG, Tampellini D, Zecca L (1999) The structure of neuromelanin and its iron binding site studied by infrared spectroscopy. FEBS Lett 457:18–22

    CAS  PubMed  Google Scholar 

  • 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 103:14785–14789

    CAS  PubMed  Google Scholar 

  • 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 28:283–291

    CAS  PubMed  Google Scholar 

  • 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 114:1872–1876

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cowen D (1986) The melanoneurons of the human cerebellum (nucleus pigmentosus cerebellaris) and homologues in the monkey. J Neuropathol Exp Neurol 45:205–221

    CAS  PubMed  Google Scholar 

  • 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 S5:2

  • D’Amato RJ, Lipman ZP, Snyder SH (1986) Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+binds to neuromelanin. Science 231:987–989

    PubMed  Google Scholar 

  • DeMattei M, Levi AC, Fariello RG (1986) Neuromelanic pigment in substantia nigra neurons of rats and dogs. Neurosci Lett 72:37–42

    CAS  PubMed  Google Scholar 

  • Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, Marsden CD (1987) Increased nigral iron content in postmortem parkinsonian brain. Lancet 2:1219–1220

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • 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 75:2583–2589

    CAS  PubMed  Google Scholar 

  • 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 24:621–628

    CAS  PubMed  Google Scholar 

  • 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 66:489–494

    CAS  PubMed  Google Scholar 

  • 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 24:398–414

    Google Scholar 

  • Earle KM (1968) Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1–14

    CAS  PubMed  Google Scholar 

  • 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:e48490

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 7:83–100

    CAS  PubMed  Google Scholar 

  • Enochs WS, Petherick P, Bogdanova A, Mohr U, Weissleder R (1997) Paramagnetic metal scavenging by melanin: MR imaging. Radiology 204:417–423

    CAS  PubMed  Google Scholar 

  • Fasano M, Bergamasco B, Lopiano L (2006) Modifications of the iron-neuromelanin system in Parkinson’s disease. J Neurochem 96:909–916

    CAS  PubMed  Google Scholar 

  • 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 86:1142–1148

    CAS  PubMed  Google Scholar 

  • Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301

    PubMed  Google Scholar 

  • 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 92:990–995

    CAS  PubMed  Google Scholar 

  • 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 113:735–739

    CAS  PubMed  Google Scholar 

  • Fellman JH (1958) Epinephrine metabolites and pigmentation in the central nervous system in a case of phenylpyruvic oligophrenia. J Neurol Neurosurg Psychiatry 21:58–62

    CAS  PubMed  Google Scholar 

  • Fenichel GM, Bazelon M (1968) Studies on neuromelanin. II. Melanin in the brainstems of infants and children. Neurology 18:817–820

    CAS  PubMed  Google Scholar 

  • 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 18:81–93

    CAS  PubMed  Google Scholar 

  • 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 17:586–598

    CAS  PubMed  Google Scholar 

  • Foppoli C, Coccia R, Cini C, Rosei MA (1997) Catecholamines oxidation by xanthine oxidase. Biochim Biophys Acta 1334:200–206

    CAS  PubMed  Google Scholar 

  • 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 25:451–454

    CAS  PubMed  Google Scholar 

  • Galzigna L, De Iuliis A, Zanatta L (2000) Enzymatic dopamine peroxidation in substantia nigra of human brain. Clin Chim Acta 300:131–138

    CAS  PubMed  Google Scholar 

  • 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 65:923–926

    CAS  PubMed  Google Scholar 

  • 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 581:283–291

    CAS  PubMed  Google Scholar 

  • 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 54:388–396

    CAS  PubMed  Google Scholar 

  • 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 593:343–346

    CAS  PubMed  Google Scholar 

  • 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 20:239–247

    CAS  PubMed  Google Scholar 

  • Graham DG (1979) On the origin and significance of neuromelanin. Arch Pathol Lab Med 103:359–362

    CAS  PubMed  Google Scholar 

  • 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 93:246–256

    CAS  PubMed  Google Scholar 

  • Haavik J (1997) L-DOPA is a substrate for tyrosine hydroxylase. J Neurochem 69:1720–1728

    CAS  PubMed  Google Scholar 

  • 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 113:721–728

    CAS  PubMed  Google Scholar 

  • Hastings TG (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 64:919–924

    CAS  PubMed  Google Scholar 

  • Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348

    CAS  PubMed  Google Scholar 

  • 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 253:198–200

    CAS  PubMed  Google Scholar 

  • Ito S (2006) Encapsulation of a reactive core in neuromelanin. Proc Natl Acad Sci USA 103:14647–14648

    CAS  PubMed  Google Scholar 

  • Ito S, Wakamatsu K (2008) Chemistry of mixed melanogenesis–pivotal roles of dopaquinone. Photochem Photobiol 84:582–592

    CAS  PubMed  Google Scholar 

  • 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 59:1168–1171

    CAS  PubMed  Google Scholar 

  • Karlsson O, Lindquist NG (2013) Melanin affinity and its possible role in neurodegeneration. J Neural Transm [Epub ahead of print]

  • 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 22:120–130

    CAS  PubMed  Google Scholar 

  • 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 59:1080–1109

    CAS  PubMed  Google Scholar 

  • 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 142:73–83

    CAS  PubMed  Google Scholar 

  • 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 20:6309–6316

    CAS  PubMed  Google Scholar 

  • 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 75:3135–3142

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 123:366–373

    PubMed  Google Scholar 

  • 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 46:598–605

    CAS  PubMed  Google Scholar 

  • Larsson BS (1993) Interaction between chemicals and melanin. Pigment Cell Res 6:127–133

    CAS  PubMed  Google Scholar 

  • 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 473:97–106

    CAS  PubMed  Google Scholar 

  • Lindquist NG, Larsson BS, Lydén-Sokolowski A (1987) Neuromelanin and its possible protective and destructive properties. Pigment Cell Res 1:133–136

    CAS  PubMed  Google Scholar 

  • Lindquist NG, Larsson BS, Lyden-Sokolowski A (1988) Autoradiography of [14C]paraquat or [14C]diquat in frogs and mice: accumulation in neuromelanin. Neurosci Lett 93:1–6

    CAS  PubMed  Google Scholar 

  • Liu Y, Edwards RH (1997) The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci 20:125–156

    CAS  PubMed  Google Scholar 

  • Ma SY, Röytt M, Collan Y, Rinne JO (1999) Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 25:394–399

    CAS  PubMed  Google Scholar 

  • Makin OS, Serpell LC (2005) Structures for amyloid fibrils. FEBS J 272:5950–5961

    CAS  PubMed  Google Scholar 

  • Mann DM, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 21:193–203

    CAS  PubMed  Google Scholar 

  • Marsden CD (1961) Pigmentation in the nucleus substantiae nigrae of mammals. J Anat 95:256–261

    CAS  PubMed  Google Scholar 

  • Marsden CD (1983) Neuromelanin and Parkinson’s disease. J Neural Transm Suppl 19:121–141

    CAS  PubMed  Google Scholar 

  • 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 64:1645–1654

    CAS  PubMed  Google Scholar 

  • Matzuk MM, Saper CB (1985) Preservation of hypothalamic dopaminergic neurons in Parkinson’s disease. Ann Neurol 18:552–555

    CAS  PubMed  Google Scholar 

  • McGeer PL, McGeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34:33–35

    CAS  PubMed  Google Scholar 

  • 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 38:1285–1291

    CAS  PubMed  Google Scholar 

  • Meredith P, Sarna T (2006) The physical and chemical properties of eumelanin. Pigment Cell Res 19:572–594

    CAS  PubMed  Google Scholar 

  • 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 43:283–287

    CAS  PubMed  Google Scholar 

  • 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 465:118–122

    CAS  PubMed  Google Scholar 

  • 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 36:2503–2508

    CAS  PubMed  Google Scholar 

  • Nicolis S, Zucchelli M, Monzani E, Casella L (2008) Myoglobin modification by enzyme-generated dopamine reactive species. Chem Eur J 14:8661–8673

    CAS  PubMed  Google Scholar 

  • 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 12:116

    PubMed Central  PubMed  Google Scholar 

  • 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 541:93–98

    CAS  PubMed  Google Scholar 

  • Okun MR (1997) The role of peroxidase in neuromelanin synthesis: a review. Physiol Chem Phys Med NMR 29:15–22

    CAS  PubMed  Google Scholar 

  • Östergren A, Annas A, Skog K, Lindquist NG, Brittebo EB (2004) Long-term retention of neurotoxic beta-carbolines in brain neuromelanin. J Neural Transm 111:141–157

    PubMed  Google Scholar 

  • 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 54:30–33

    CAS  PubMed  Google Scholar 

  • Rabey JM, Hefti F (1990) Neuromelanin synthesis in rat and human substantia nigra. J Neural Transm Park Dis Dement Sect. 2:1–14

    CAS  PubMed  Google Scholar 

  • 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 37:2403–2407

    CAS  PubMed  Google Scholar 

  • 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 6:287

    Google Scholar 

  • 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 17:1215–1218

    PubMed  Google Scholar 

  • 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 26:1633–1638

    PubMed  Google Scholar 

  • 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 111:1253–1265

    CAS  PubMed  Google Scholar 

  • 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 113:633–644

    CAS  PubMed  Google Scholar 

  • 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 23:110–119

    CAS  PubMed  Google Scholar 

  • 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 York

    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

    CAS  PubMed  Google Scholar 

  • Sulzer D, Zecca L (2000) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1:181–195

    CAS  PubMed  Google Scholar 

  • 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 97:11869–11874

    CAS  PubMed  Google Scholar 

  • 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 106:24–36

    CAS  PubMed  Google Scholar 

  • Swartz HM, Sarna T, Zecca L (1992) Modulation by neuromelanin of the availability and reactivity of metal ions. Ann Neurol 32:S69–S75

    CAS  PubMed  Google Scholar 

  • 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 70:585–589

    CAS  PubMed  Google Scholar 

  • Tousi NS, Buck DJ, Zecca L, Davis RL (2010) Neuromelanin inhibits CXCL10 expression in human astroglial cells. Neurosci Lett 486:47–50

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 4:945–957

    CAS  PubMed  Google Scholar 

  • 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 72:51–55

    CAS  PubMed  Google Scholar 

  • Van Woert MH, Prasad KN, Borg DC (1967) Spectroscopic studies of substantia nigra pigment in human subjects. J Neurochem 14:707–716

    PubMed  Google Scholar 

  • 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 37:358–369

    CAS  PubMed  Google Scholar 

  • Wakamatsu K, Ito S (2002) Advanced chemical methods in melanin determination. Pigment Cell Res 15:174–183

    CAS  PubMed  Google Scholar 

  • Wakamatsu K, Fujikawa K, Zucca FA, Zecca L, Ito S (2003) The structure of neuromelanin as studied by chemical degradative methods. J Neurochem 86:1015–1023

    CAS  PubMed  Google Scholar 

  • Wakamatsu K, Murase T, Zucca FA, Zecca L, Ito S (2012) Biosynthetic pathway to neuromelanin and its aging process. Pigment Cell Melanoma Res 25:792–803

    CAS  PubMed  Google Scholar 

  • 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 48:1457–1462

    CAS  PubMed  Google Scholar 

  • 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 17:500–502

    CAS  PubMed  Google Scholar 

  • 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 45:159–162

    CAS  PubMed  Google Scholar 

  • Yamamoto T, Anno M, Sato T (1987) Effects of paraquat on mitochondria of rat skeletal muscle. Comp Biochem Physiol C 86:375–378

    CAS  PubMed  Google Scholar 

  • 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 126:47–54

    CAS  PubMed  Google Scholar 

  • 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 1271:343–348

    PubMed  Google Scholar 

  • 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 62:1097–1101

    CAS  PubMed  Google Scholar 

  • 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 73:407–415

    CAS  PubMed  Google Scholar 

  • 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 74:1758–1765

    CAS  PubMed  Google Scholar 

  • 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 249:449–454

    CAS  Google Scholar 

  • 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 76:1766–1773

    CAS  PubMed  Google Scholar 

  • 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 510:216–220

    CAS  PubMed  Google Scholar 

  • 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 101:9843–9984

    CAS  PubMed  Google Scholar 

  • 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 105:17567–17572

    CAS  PubMed  Google Scholar 

  • 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 106:1866–1875

    CAS  PubMed  Google Scholar 

  • 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 116:47–55

    CAS  PubMed  Google Scholar 

  • 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 19:63–72

    PubMed Central  PubMed  Google Scholar 

  • 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) 1:1–11

    Google Scholar 

  • 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 113:757–767

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Institute of Biomedical Technologies, National Research Council of Italy, Via Cervi, 93, 20090, Segrate (MI), Italy

    Fabio A. Zucca, Emy Basso, Francesca A. Cupaioli, Emanuele Ferrari & Luigi Zecca

  2. Department of Chemistry, University of Pavia, 27100, Pavia, Italy

    Luigi Casella

  3. Department of Psychiatry, Neurology and Pharmacology, Columbia University, New York, NY, 10032, USA

    David Sulzer

Authors
  1. Fabio A. Zucca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emy Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca A. Cupaioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emanuele Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Sulzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luigi Casella
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luigi Zecca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luigi Zecca.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zucca, F.A., Basso, E., Cupaioli, F.A. et al. Neuromelanin of the Human Substantia Nigra: An Update. Neurotox Res 25, 13–23 (2014). https://doi.org/10.1007/s12640-013-9435-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-013-9435-y

Keywords

Search

Navigation