Abstract
Neuromelanin is supposed to play a key role in the pathogenesis of Parkinson’s disease. A common theory is the formation of reactive oxygen species through the Fenton reaction catalyzed by neuromelanin-bound iron ions and subsequent death of the dopaminergic cells in the substantia nigra. From a physicochemical point of view, this pathway is rather implausible: a highly reactive radical built within a powerful radical scavenger would more promptly be inactivated before it might diffuse within the cell to reach a target to exert its deleterious potential. This review of the literature provides evidence for an interaction of neuromelanin with the calcium signaling pathway in Parkinson’s disease and expands the view of the pathophysiological contribution of neuromelanin towards a cytoprotective involvement of this macromolecule in the calcium signaling system. More probably than being directly involved in the production of reactive oxygen species, neuromelanin may act as a calcium reservoir and thus protect dopaminergic cells from cell death. A loss of neuromelanin, as observed in the substantia nigra of Parkinson patients, would lead to enhanced calcium messaging through the loss of an important calcium reservoir and thus finally via the formation of reactive oxygen species to cell death within the substantia nigra.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219. https://doi.org/10.1038/nrn1868
Ben-Shachar D, Riederer P, Youdim MB (1991) Iron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease. J Neurochem 57:1609–1614
Blanckenberg J, Bardien S, Glanzmann B, Okubadejo NU, Carr JA (2013) The prevalence and genetics of Parkinson’s disease in sub-Saharan Africans. J Neurol Sci 335:22–25. https://doi.org/10.1016/j.jns.2013.09.010
Breathnach AS (1988) Extra-cutaneous melanin. Pigment Cell Res 1:234–237
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
Bush WD, Simon JD (2007) Quantification of Ca2+ binding to melanin supports the hypothesis that melanosomes serve a functional role in regulating calcium homeostasis. Pigment Cell Res 20:134–139. https://doi.org/10.1111/j.1600-0749.2007.00362.x
Bustamante J, Bredeston L, Malanga G, Mordoh J (1993) Role of melanin as a scavenger of active oxygen species. Pigment Cell Res 6:348–353
Cacabelos R (2017) Parkinson's disease: from pathogenesis to pharmacogenomics. Int J Mol Sci 18(3):551. https://doi.org/10.3390/ijms18030551
Curtin JF et al (2006) Fms-like tyrosine kinase 3 ligand recruits plasmacytoid dendritic cells to the brain. J Immunol 176:3566–3577
Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain: II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain J Neurol 122(Pt 8):1437–1448
DeMattei M, Levi AC, Fariello RG (1986) Neuromelanic pigment in substantia nigra neurons of rats and dogs. Neurosci Lett 72:37–42
Depboylu C, Schäfer MK, Arias-Carrion O, Oertel WH, Weihe E, Höglinger GU (2011) Possible involvement of complement factor C1q in the clearance of extracellular neuromelanin from the substantia nigra in Parkinson disease. J Neuropathol Exp Neurol 70:125–132. https://doi.org/10.1097/NEN.0b013e31820805b9
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
Double KL, Dedov VN, Fedorow H, Kettle E, Halliday GM, Garner B, Brunk UT (2008) The comparative biology of neuromelanin and lipofuscin in the human brain. Cell Mol Life Sci 65:1669–1682. https://doi.org/10.1007/s00018-008-7581-9
Double KL et al (2009) Anti-melanin antibodies are increased in sera in Parkinson’s disease. Exp Neurol 217:297–301. https://doi.org/10.1016/j.expneurol.2009.03.002
Dräger UC (1985) Calcium binding in pigmented and albino eyes. Proc Natl Acad Sci U S A 82:6716–6720
Dunford R, Land EJ, Rozanowska M, Sarna T, Truscott TG (1995) Interaction of melanin with carbon- and oxygen-centered radicals from methanol and ethanol. Free Radic Biol Med 19:735–740
Engelen M et al (2012) Neuromelanins of human brain have soluble and insoluble components with dolichols attached to the melanic structure. PloS One 7:e48490. https://doi.org/10.1371/journal.pone.0048490
Fasano M, Bergamasco B, Lopiano L (2006) Modifications of the iron-neuromelanin system in Parkinson’s disease. J Neurochem 96:909–916. https://doi.org/10.1111/j.1471-4159.2005.03638.x
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
Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, Double KL (2005) Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson’s disease. Prog Neurobiol 75:109–124. https://doi.org/10.1016/j.pneurobio.2005.02.001
Ferrari E et al (2013) Synthesis and structural characterization of soluble neuromelanin analogs provides important clues to its biosynthesis. J Biol Inorg Chem 18:81–93. https://doi.org/10.1007/s00775-012-0951-7
Ferrari E et al (2017) Synthesis, structure characterization, and evaluation in microglia cultures of neuromelanin analogues suitable for modeling Parkinson’s disease. ACS Chem Neurosci 8:501–512. https://doi.org/10.1021/acschemneuro.6b00231
Foppoli C, Coccia R, Cini C, Rosei MA (1997) Catecholamines oxidation by xanthine oxidase. Biochim Biophys Acta 1334:200–206
Galazka-Friedman J, Friedman A (2011) Role of iron in pathogenesis of Parkinson disease. BioTechnol 92:153–158
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
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
Gill SS, Salt AN (1997) Quantitative differences in endolymphatic calcium and endocochlear potential between pigmented and albino guinea pigs. Hear Res 113:191–197
Halliday GM et al (2005) Alpha-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson’s disease. Brain J Neurol 128:2654–2664. https://doi.org/10.1093/brain/awh584
Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348. https://doi.org/10.1038/334345a0
Hirsch EC, Graybiel AM, Agid Y (1989) Selective vulnerability of pigmented dopaminergic neurons in Parkinson’s disease. Acta Neurol Scand Suppl 126:19–22
Hoogduijn MJ, Smit NP, van der Laarse A, van Nieuwpoort AF, Wood JM, Thody AJ (2003) Melanin has a role in Ca2+ homeostasis in human melanocytes. Pigment Cell Res 16:127–132
Hoogduijn MJ, Cemeli E, Ross K, Anderson D, Thody AJ, Wood JM (2004) Melanin protects melanocytes and keratinocytes against H2O2-induced DNA strand breaks through its ability to bind Ca2+. Exp Cell Res 294:60–67. https://doi.org/10.1016/j.yexcr.2003.11.007
Hurley MJ, Brandon B, Gentleman SM, Dexter DT (2013) Parkinson’s disease is associated with altered expression of CaV1 channels and calcium-binding proteins. Brain J Neurol 136:2077–2097. https://doi.org/10.1093/brain/awt134
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
Ings RM (1984) The melanin binding of drugs and its implications. Drug Metab Rev 15:1183–1212. https://doi.org/10.3109/03602538409033561
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
Karlsson O, Lindquist NG (2016) Melanin and neuromelanin binding of drugs and chemicals: toxicological implications. Arch Toxicol 90:1883–1891. https://doi.org/10.1007/s00204-016-1757-0
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 59:1080–1089
Korytowski W, Sarna T, Zareba M (1995) Antioxidant action of neuromelanin: the mechanism of inhibitory effect on lipid peroxidation. Arch Bioch Biophys 319:142–148
Larsson BS (1993) Interaction between chemicals and melanin. Pigment Cell Res 6:127–133
Liu Y, Hong L, Kempf VR, Wakamatsu K, Ito S, Simon JD (2004) Ion-exchange and adsorption of Fe(III) by Sepia melanin. Pigment Cell Res 17:262–269. https://doi.org/10.1111/j.1600-0749.2004.00140.x
Mann DM, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 21:193–203
Marsden CD (1961) Pigmentation in the nucleus substantiae nigrae of mammals. J Anat 95:256–261
Marttila RJ, Rinne UK (1981) Epidemiology of Parkinson’s disease—an overview. J Neural Transm 51:135–148
Meyer zum Gottesberge AM (1988) Physiology and pathophysiology of inner ear melanin. Pigment Cell Res 1:238–249
Miranda M, Botti D, Bonfigli A, Ventura T, Arcadi A (1984) Tyrosinase-like activity in normal human substantia nigra. Gen Pharmacol 15:541–544
Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Ann Rev Neurosci 28:57–87. https://doi.org/10.1146/annurev.neuro.28.061604.135718
Nicolaus BJ (2005) A critical review of the function of neuromelanin and an attempt to provide a unified theory. Med Hypotheses 65:791–796. https://doi.org/10.1016/j.mehy.2005.04.011
Oberländer U et al (2011) Neuromelanin is an immune stimulator for dendritic cells in vitro. BMC Neurosci 12:116. https://doi.org/10.1186/1471-2202-12-116
Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain J Neurol 128:2665–2674. https://doi.org/10.1093/brain/awh625
Pan T, Zhu J, Hwu WJ, Jankovic J (2012) The role of alpha-synuclein in melanin synthesis in melanoma and dopaminergic neuronal cells. PloS One 7:e45183. https://doi.org/10.1371/journal.pone.0045183
Panessa BJ, Zadunaisky E (1981) Pigment granules: a calcium reservoir in the vertebrate eye. Exp Eye Res 32:593–604
Pilas B, Sarna T, Kalyanaraman B, Swartz HM (1988) The effect of melanin on iron associated decomposition of hydrogen peroxide. Free Radic Biol Med 4:285–293
Poewe W et al (2017) Parkinson disease. Nat Rev Dis Prim 3:17013. https://doi.org/10.1038/nrdp.2017.13
Reimao S et al (2016) Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early-stage Parkinson’s disease. Eur J Neurol 23:368–374. https://doi.org/10.1111/ene.12838
Rosei MA, Blarzino C, Foppoli C, Mosca L, Coccia R (1994) Lipoxygenase-catalyzed oxidation of catecholamines. Biochem Biophys Res Commun 200:344–350. https://doi.org/10.1006/bbrc.1994.1454
Rosei MA, Blarzino C, Coccia R, Foppoli C, Mosca L, Cini C (1998) Production of melanin pigments by cytochrome c/H2O2 system. Int J Biochem Cell Biol 30:457–463
Rozanowska M, Sarna T, Land EJ, Truscott TG (1999) Free radical scavenging properties of melanin interaction of eu- and pheo-melanin models with reducing and oxidising radicals. Free Radic Biol Med 26:518–525
Salceda R, Sanchez-Chavez G (2000) Calcium uptake, release and ryanodine binding in melanosomes from retinal pigment epithelium. Cell Calcium 27:223–229. https://doi.org/10.1054/ceca.2000.0111
Saran M, Michel C, Stettmaier K, Bors W (2000) Arguments against the significance of the Fenton reaction contributing to signal pathways under in vivo conditions. Free Radic Res 33:567–579
Sarna T, Pilas B, Land EJ, Truscott TG (1986) Interaction of radicals from water radiolysis with melanin. Biochim Biophys Acta 883:162–167
Schmidt SY, Peisch RD (1986) Melanin concentration in normal human retinal pigment epithelium. Regional variation and age-related reduction. Investig Ophthalmol Vis Sci 27:1063–1067
Schroeder RL, Double KL, Gerber JP (2015) Using Sepia melanin as a PD model to describe the binding characteristics of neuromelanin—a critical review. J Chem Neuroanat 64-65:20–32. https://doi.org/10.1016/j.jchemneu.2015.02.001
Segura-Aguilar J, Paris I, Munoz P, Ferrari E, Zecca L, Zucca FA (2014) Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem 129:898–915. https://doi.org/10.1111/jnc.12686
Sian-Hülsmann J, Mandel S, Youdim MB, Riederer P (2011) The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem 118:939–957. https://doi.org/10.1111/j.1471-4159.2010.07132.x
Sies H (1993) Strategies of antioxidant defense. Eur J Biochem 215:213–219
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
Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–250. https://doi.org/10.1016/j.tins.2007.03.009
Sulzer D, Zecca L (2000) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1:181–195
Sulzer D et al (2000) Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci U S A 97:11869–11874. https://doi.org/10.1073/pnas.97.22.11869
Surmeier DJ (2007) Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet Neurol 6:933–938. https://doi.org/10.1016/s1474-4422(07)70246-6
Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA (2011) The origins of oxidant stress in Parkinson’s disease and therapeutic strategies. Antioxid Redox Signal 14:1289–1301. https://doi.org/10.1089/ars.2010.3521
Tada M, Kohno M, Niwano Y (2010) Scavenging or quenching effect of melanin on superoxide anion and singlet oxygen. J Clin Biochem Nutr 46:224–228. https://doi.org/10.3164/jcbn.09-84
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
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
Xu S, Chan P (2015) Interaction between neuromelanin and alpha-synuclein in Parkinson’s disease. Biomolecules 5:1122–1142. https://doi.org/10.3390/biom5021122
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
Yamada T, McGeer PL, Baimbridge KG, McGeer EG (1990) Relative sparing in Parkinson’s disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res 526:303–307
Zaichick SV, McGrath KM, Caraveo G (2017) The role of Ca2+ signaling in Parkinson’s disease. Dis Models Mech 10:519–535. https://doi.org/10.1242/dmm.028738
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
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
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
Zecca L, Tampellini D, Gerlach M, Riederer P, Fariello RG, Sulzer D (2001) Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. Mol Pathol 54:414–418
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
Zecca L et al (2008) 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. https://doi.org/10.1111/j.1471-4159.2008.05541.x
Zhang W et al (2011) Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res 19:63–72. https://doi.org/10.1007/s12640-009-9140-z
Zucca FA et al (2015) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. https://doi.org/10.1016/j.pneurobio.2015.09.012
Zündorf G, Reiser G (2011) Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid Redox Signal 14:1275–1288. https://doi.org/10.1089/ars.2010.3359
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The author declares that he has no conflict of interest.
Rights and permissions
About this article
Cite this article
Knörle, R. Neuromelanin in Parkinson’s Disease: from Fenton Reaction to Calcium Signaling. Neurotox Res 33, 515–522 (2018). https://doi.org/10.1007/s12640-017-9804-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-017-9804-z