Neuromelanin of the human substantia Nigra: An update

Neurotoxicity Research

Volumn 25, Issue 1, 2014, Pages 13-23

  Zucca, Fabio A ^a   Basso, Emy ^a   Cupaioli, Francesca A ^a   Ferrari, Emanuele ^a   Sulzer, David ^c   Casella, Luigi ^b   Zecca, Luigi ^a  

^a CNR   (Italy)

^b UNIVERSITY OF PAVIA   (Italy)

^c Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

Aging; Neurodegeneration; Neuroinflammation; Neuromelanin; Parkinson's disease; Substantia nigra

Indexed keywords

1 METHYL 4 PHENYLPYRIDINIUM; 1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ALUMINUM; CADMIUM; COBALT; COPPER; IRON; LEAD; MANGANESE; MERCURY; NEUROMELANIN; PARAQUAT; SELENIUM; UBIQUITIN; ZINC; MELANIN;

AUTOPSY; BINDING AFFINITY; CELL ACTIVATION; CELL ORGANELLE; DOPAMINERGIC NERVE CELL; HUMAN; MICROGLIA; NERVE DEGENERATION; NEUROPROTECTION; PARKINSON DISEASE; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN SYNTHESIS; PROTEOMICS; REVIEW; SIGNAL TRANSDUCTION; SUBSTANTIA NIGRA; TOXICITY; BIOSYNTHESIS; CHEMISTRY; METABOLISM;

DOPAMINERGIC NEURONS; HUMANS; MELANINS; SUBSTANTIA NIGRA;

EID: 84891859053     PISSN: 10298428     EISSN: 14763524     Source Type: Journal    
DOI: 10.1007/s12640-013-9435-y     Document Type: Review

References (127)

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 1361:49-58 (Pubitemid 27281643)
2. Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov Disord 13:221-227 (Pubitemid 28127795)
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 29:225-240
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 30:650-667
5. Bazelon M, Fenichel GM, Randall J (1967) Studies on neuromelanin. I. A melanin system in the human adult brainstem. Neurology 17:512-519
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 114:419-424 (Pubitemid 47500354)
7. Bogerts B (1981) A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker. J Comp Neurol 197:63-80 (Pubitemid 11096585)
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 80:9557-9566
9. Bridelli MG, Tampellini D, Zecca L (1999) The structure of neuromelanin and its iron binding site studied by infrared spectroscopy. FEBS Lett 457:18-22 (Pubitemid 29387401)
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 103:14785-14789 (Pubitemid 44527806)
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 28:283-291 (Pubitemid 34989290)
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 114:1872-1876 (Pubitemid 44873688)
13. Cowen D (1986) The melanoneurons of the human cerebellum (nucleus pigmentosus cerebellaris) and homologues in the monkey. J Neuropathol Exp Neurol 45:205-221 (Pubitemid 16061963)
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 5:2
15. D'Amato RJ, Lipman ZP, Snyder SH (1986) Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+binds to neuromelanin. Science 231:987-989 (Pubitemid 16046616)
16. DeMattei M, Levi AC, Fariello RG (1986) Neuromelanic pigment in substantia nigra neurons of rats and dogs. Neurosci Lett 72:37-42 (Pubitemid 17184913)
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 2:1219-1220 (Pubitemid 17156630)
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 52:1830-1836 (Pubitemid 19140770)
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 75:2583-2589
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 24:621-628 (Pubitemid 35013523)
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 66:489-494 (Pubitemid 36937034)
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 24:398-414
23. Earle KM (1968) Studies on Parkinson's disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1-14
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:e48490
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 7:83-100
26. Enochs WS, Petherick P, Bogdanova A, Mohr U, Weissleder R (1997) Paramagnetic metal scavenging by melanin: MR imaging. Radiology 204:417-423 (Pubitemid 27337488)
27. Fasano M, Bergamasco B, Lopiano L (2006) Modifications of the iron-neuromelanin system in Parkinson's disease. J Neurochem 96:909-916
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 86:1142-1148 (Pubitemid 37022190)
29. Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114:2283-2301
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 92:990-995 (Pubitemid 40229570)
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 113:735-739 (Pubitemid 43847166)
32. Fellman JH (1958) Epinephrine metabolites and pigmentation in the central nervous system in a case of phenylpyruvic oligophrenia. J Neurol Neurosurg Psychiatry 21:58-62
33. Fenichel GM, Bazelon M (1968) Studies on neuromelanin. II. Melanin in the brainstems of infants and children. Neurology 18:817-820
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 18:81-93
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 17:586-598
36. Foppoli C, Coccia R, Cini C, Rosei MA (1997) Catecholamines oxidation by xanthine oxidase. Biochim Biophys Acta 1334:200-206 (Pubitemid 27117522)
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 25:451-454 (Pubitemid 16109584)
38. Galzigna L, De Iuliis A, Zanatta L (2000) Enzymatic dopamine peroxidation in substantia nigra of human brain. Clin Chim Acta 300:131-138 (Pubitemid 30665780)
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 65:923-926
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 581:283-291
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 54:388-396
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 593:343-346
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 20:239-247
44. Graham DG (1979) On the origin and significance of neuromelanin. Arch Pathol Lab Med 103:359-362 (Pubitemid 10248819)
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 93:246-256 (Pubitemid 40463533)
46. Haavik J (1997) L-DOPA is a substrate for tyrosine hydroxylase. J Neurochem 69:1720-1728 (Pubitemid 27406973)
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 113:721-728 (Pubitemid 43847164)
48. Hastings TG (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 64:919-924
49. Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334:345-348
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 253:198-200 (Pubitemid 28442597)
51. Ito S (2006) Encapsulation of a reactive core in neuromelanin. Proc Natl Acad Sci USA 103:14647-14648 (Pubitemid 44527784)
52. Ito S, Wakamatsu K (2008) Chemistry of mixed melanogenesis-pivotal roles of dopaquinone. Photochem Photobiol 84:582-592 (Pubitemid 351589353)
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 59:1168-1171
54. Karlsson O, Lindquist NG (2013) Melanin affinity and its possible role in neurodegeneration. J Neural Transm [Epub ahead of print]
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 22:120-130
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 59:1080-1109
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 142:73-83 (Pubitemid 16244288)
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 20:6309-6316 (Pubitemid 30658427)
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 75:3135-3142 (Pubitemid 28548982)
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 123:366-373 (Pubitemid 30055159)
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 46:598-605 (Pubitemid 29466438)
62. Larsson BS (1993) Interaction between chemicals and melanin. Pigment Cell Res 6:127-133
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 473:97-106 (Pubitemid 38507122)
64. Lindquist NG, Larsson BS, Lydén-Sokolowski A (1987) Neuromelanin and its possible protective and destructive properties. Pigment Cell Res 1:133-136
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 93:1-6
66. Liu Y, Edwards RH (1997) The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci 20:125-156 (Pubitemid 27106378)
67. Ma SY, Röytt M, Collan Y, Rinne JO (1999) Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 25:394-399 (Pubitemid 29495687)
68. Makin OS, Serpell LC (2005) Structures for amyloid fibrils. FEBS J 272:5950-5961 (Pubitemid 41713687)
69. Mann DM, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson's disease. Mech Ageing Dev 21:193-203 (Pubitemid 13058093)
70. Marsden CD (1961) Pigmentation in the nucleus substantiae nigrae of mammals. J Anat 95:256-261
71. Marsden CD (1983) Neuromelanin and Parkinson's disease. J Neural Transm Suppl 19:121-141
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 64:1645-1654
73. Matzuk MM, Saper CB (1985) Preservation of hypothalamic dopaminergic neurons in Parkinson's disease. Ann Neurol 18:552-555 (Pubitemid 16258089)
74. McGeer PL, McGeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34:33-35 (Pubitemid 8020106)
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 38:1285-1291
76. Meredith P, Sarna T (2006) The physical and chemical properties of eumelanin. Pigment Cell Res 19:572-594 (Pubitemid 44674110)
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 43:283-287 (Pubitemid 28113589)
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 465:118-122
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 36:2503-2508 (Pubitemid 15072756)
80. Nicolis S, Zucchelli M, Monzani E, Casella L (2008) Myoglobin modification by enzyme-generated dopamine reactive species. Chem Eur J 14:8661-8673
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 12:116
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 541:93-98
83. Okun MR (1997) The role of peroxidase in neuromelanin synthesis: a review. Physiol Chem Phys Med NMR 29:15-22 (Pubitemid 127516785)
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 111:141-157 (Pubitemid 38283225)
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 54:30-33
86. Rabey JM, Hefti F (1990) Neuromelanin synthesis in rat and human substantia nigra. J Neural Transm Park Dis Dement Sect. 2:1-14 (Pubitemid 20215377)
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 37:2403-2407 (Pubitemid 8399815)
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 6:287
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 17:1215-1218 (Pubitemid 44051416)
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 26:1633-1638
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 111:1253-1265 (Pubitemid 39468389)
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 113:633-644 (Pubitemid 43673603)
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 23:110-119 (Pubitemid 27217014)
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 York
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 74:199-205
96. Sulzer D, Zecca L (2000) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1:181-195
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 97:11869-11874
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 106:24-36 (Pubitemid 351850210)
99. Swartz HM, Sarna T, Zecca L (1992) Modulation by neuromelanin of the availability and reactivity of metal ions. Ann Neurol 32:S69-S75
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 70:585-589 (Pubitemid 26226682)
101. Tousi NS, Buck DJ, Zecca L, Davis RL (2010) Neuromelanin inhibits CXCL10 expression in human astroglial cells. Neurosci Lett 486:47-50
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 4:945-957 (Pubitemid 41309152)
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 72:51-55
104. Van Woert MH, Prasad KN, Borg DC (1967) Spectroscopic studies of substantia nigra pigment in human subjects. J Neurochem 14:707-716
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 37:358-369
106. Wakamatsu K, Ito S (2002) Advanced chemical methods in melanin determination. Pigment Cell Res 15:174-183 (Pubitemid 34608975)
107. Wakamatsu K, Fujikawa K, Zucca FA, Zecca L, Ito S (2003) The structure of neuromelanin as studied by chemical degradative methods. J Neurochem 86:1015-1023 (Pubitemid 36988812)
108. Wakamatsu K, Murase T, Zucca FA, Zecca L, Ito S (2012) Biosynthetic pathway to neuromelanin and its aging process. Pigment Cell Melanoma Res 25:792-803
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 48:1457-1462 (Pubitemid 47312008)
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 17:500-502
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 45:159-162 (Pubitemid 27182239)
112. Yamamoto T, Anno M, Sato T (1987) Effects of paraquat on mitochondria of rat skeletal muscle. Comp Biochem Physiol C 86:375-378 (Pubitemid 17021790)
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 126:47-54 (Pubitemid 20022076)
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 1271:343-348
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 62:1097-1101 (Pubitemid 24064524)
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 73:407-415 (Pubitemid 26169932)
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 74:1758-1765 (Pubitemid 30163999)
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 249:449-454 (Pubitemid 32772323)
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 76:1766-1773 (Pubitemid 32221116)
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 510:216-220 (Pubitemid 34093828)
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 101:9843-9984
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 105:17567-17572
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 106:1866-1875
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 116:47-55
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 19:63-72
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) 1:1-11
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 113:757-767 (Pubitemid 43847169)