Functional effects of neuromelanin and synthetic melanin in model systems Article First Online: 05 May 2006 Received: 01 September 2005 Accepted: 24 February 2006 DOI:
Cite this article as: Double, K. J Neural Transm (2006) 113: 751. doi:10.1007/s00702-006-0450-5 Summary.
The function of the dark polymer pigment neuromelanin found in catecholaminergic neurons of the human brain is not understood, especially as most published data are based upon a synthetic model melanin which differs structurally to the native pigment. Nevertheless human neuromelanin has been shown to efficiently bind transition metals such as iron, as well as other potentially toxic molecules. The pigment may have a protective function in the healthy brain by, for example, contributing to iron homeostasis within pigmented nuclei. We have demonstrated that synthetic dopamine melanin stimulates cell damage in both cell lines and primary cells in vitro, an effect associated with increased hydroxyl radical production and apoptosis. In contrast, at low iron concentrations native neuromelanin does not induce cell damage but rather protects cells in culture from oxidative stress. This protective function appears to be lost at high iron concentrations where neuromelanin saturated with iron functions as a source of oxidative load, rather than an iron chelator. Changes to neuromelanin and tissue iron load in Parkinson’s disease may decrease the protective potential of the pigment, thus increase the potential for cell damage in this disorder.
Keywords: Melanin, neuroprotection, Parkinson’s disease. References Aimi, Y, McGeer, PL 1996 Lack of toxicity of human neuromelanin to rat brain dopaminergic neurons Parkinson Rel Disord 2 69 74 CrossRef Google Scholar Ben-Shachar, D, Riederer, P, Youdim, MBH 1991 Iron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease J Neurochem 57 1609 1614 PubMed Google Scholar Ben-Shachar, D, Youdim, MB 1990 Selectivity of melanized nigra-striatal dopamine neurons to degeneration in Parkinson’s disease may depend on iron-melanin interaction J Neural Transm [Suppl] 29 251 258 Google Scholar Berg, MD, Gerlach, M, Youdim, MBH, Double, KL, Zecca, L, Riederer, P, Becker, G 2001 Brain iron pathways and their relevance to Parkinson’s disease J Neurochem 79 225 236 PubMed CrossRef Google Scholar Bolzoni, F, Giraudo, S, Lopiano, L, Bergamasco, B, Fasano, M, Crippa, PR 2002 Magnetic investigations of human mesencephalic neuromelanin Biochem Biophys Acta 1586 210 218 PubMed Google Scholar Double, K, Riederer, P, Gerlach, M 1999 The significance of neuromelanin in Parkinson’s disease Drug News Develop 12 333 340 Google Scholar Double, K, Zecca, L, Costo, P, Mauer, M, Greisinger, 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 PubMed CrossRef Google Scholar Double, KL, Gerlach, M, Schünemann, V, Trautwein, AX, Zecca, L, Gallorini, M, Youdim, MBH, Riederer, P, Ben-Shachar, D 2003 Iron binding characteristics of neuromelanin of the human substantia nigra Biochem Pharmacol 66 489 494 PubMed CrossRef Google Scholar Double, KL, Halliday, GM, Henderson, J, Griffiths, FM, Heinemann, T, Riederer, P, Gerlach, M 2003 The dopamine receptor agonist lisuride attenuates iron-mediated dopaminergic neurodegeneration Exp Neurol 184 530 535 PubMed CrossRef Google Scholar Fasano, M, Giraudo, S, Coha, S, Bergamasco, B, Lopiano, L 2003 Residual substantia nigra neuromelanin in Parkinson’s disease is cross-linked to alpha-synuclein Neurochem Int 42 603 606 PubMed CrossRef 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 PubMed CrossRef Google Scholar 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 PubMed CrossRef Google Scholar Hirsch, E, Graybiel, A, Agid, Y 1988 Melanized dopamine neurons are differentially susceptible to degeneration in Parkinson’s disease Nature 28 345 348 CrossRef Google Scholar Korytowski, W, Sarna, T, Zareba, M 1995 Antioxidant action of neuromelanin: the mechanism of inhibitory effect on lipid peroxidation Arch Biochem Biophys 319 142 148 PubMed CrossRef Google Scholar Li, J, Scheller, C, Koutsilieri, E, Griffiths, F, Beart, PM, Mercer, LD, Halliday, G, Kettle, E, Rowe, D, Riederer, P, Gerlach, M, Rodriguez, M, Double, KL 2005 Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and glial cells J Neurochem 95 599 608 PubMed CrossRef Google Scholar Liu, Y, Hong, L, Kempf, V, Wakamatsu, K, Ito, S, Simon, J 2004 Ion-exchange and adsorption of Fe2(III) by Sepia melanin Pigment Cell Res 17 262 269 PubMed CrossRef Google Scholar Lopiano, L, Chiesa, M, Digilio, D, Giraudo, G, Bergamasco, B, Fasano, M 2000 Q-band EPR investigations of neuromelanin in control and Parkinson’s disease patients Biochem Biophys Acta 1500 306 312 PubMed Google Scholar Offen, D, Ziv, I, Barzilai, A, Gorodin, S, Glater, E, Hochman, A, Melamed, E 1997 Dopamine-melanin induces apoptosis in PC12 cells; Possible implications for the etiology of Parkinson’s disease Neurochem Int 31 207 216 PubMed CrossRef Google Scholar Pilas, B, Sarna, T, Kalyanaraman, B, Swartz, H 1988 The effect of melanin on iron associated decomposition of hydrogen peroxide Free Radic Biol Med 4 285 293 PubMed CrossRef Google Scholar Shima, T, Sarna, T, Swartz, H, 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 PubMed CrossRef Google Scholar Wilms, H, Rosenstiel, P, Sievers, J, Deuschl, G, Zecca, L, Lucius, R 2003 Activation of microglia by human neuromelanin is NF-κB-dependent and involves p38 mitrogen-activated protein kinase: implications for Parkinson’s disease FASEB J 17 500 502 PubMed Google Scholar Youdim, M, Ben-Shachar, D, Riederer, P 1989 Is Parkinson’s disease a progressive siderosis of substantia nigra resulting from iron and melanin induced neurodegeneration? Acta Neurol Scand 126 47 54 CrossRef 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 Biochem Biophys Acta 1271 343 348 PubMed Google Scholar Zecca, L, Tampellini, D, Gatti, A, Crippa, R, Eisner, M, Sulzer, D, Ito, S, Fariello, R, Gallorini, M 2002 The neuromelanin of the human substantia nigra and its interaction with metals J Neural Transm 109 663 672 PubMed CrossRef Google Scholar Zecca, L, Zucca, FA, Wilms, H, Sulzer, D 2003 Neuromelanin of the substantia nigra: a neuronal block hole with protective and toxic characteristics Trends Neurosci 26 578 580 Google Scholar