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Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome

Journal of Neural Transmission volume 113, pages 633–644 (2006)Cite this article

Summary.

Parkinson’s disease is characterized by the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin. Involvement of neuromelanin in the pathogenesis may be either cytotoxic or protective. Recently we found that neuromelanin reduces the activity of 26S proteasome. In this paper, the detailed mechanisms behind the reduced activity were studied using neuromelanin isolated from the human brain. Neuromelanin increased the oxidative stress, but synthetic melanin did not. Superoxide dismutase and deferoxamine completely suppressed the increase, indicating that superoxide produced by an iron-mediated reaction plays a central role. Iron was shown to reduce in situ 26S proteasome activity in SH-SY5Y cells and the reduction was protected by antioxidants. These results suggest that iron released from neuromelanin increases oxidative stress in mitochondria, and then causes mitochondrial dysfunction and reduces proteasome function. The role of neuromelanin is discussed in relation to the selective vulnerability of dopamine neurons in Parkinson’s disease.

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References

  • Y Akao N Seki Y Nakagawa H Yi K Matsumoto Y Ito K Ito M Funaoka W Maruyama M Naoi Y Nozawa (2004) ArticleTitleA highly bioactive lignophenol derivative from bamboo lignin exhibits a potent activity to suppress apoptosis induced by oxidative stress in human neurobalstoma SH-SY5Y cells Bioorgan Med Chem 12 4791–4801 Occurrence Handle10.1016/j.bmc.2004.07.022 Occurrence Handle1:CAS:528:DC%2BD2cXntFSntbw%3D

    Article  CAS  Google Scholar 

  • D Ben-Shachar P Riederer MBH Youdim (1991) ArticleTitleIron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease J Neurochem 57 1609–1612 Occurrence Handle1919577 Occurrence Handle1:CAS:528:DyaK3MXmslKqtbY%3D

    PubMed  CAS  Google Scholar 

  • MM Bradford (1976) ArticleTitleA rapid and sensitive method for quantitation of microgram quantities of protein using the principle of protein dye binding Anal Biochem 72 248–254 Occurrence Handle10.1016/0003-2697(76)90527-3 Occurrence Handle942051 Occurrence Handle1:CAS:528:DyaE28XksVehtrY%3D

    Article  PubMed  CAS  Google Scholar 

  • MG Bridelli D Tampellini L Zecca (1999) ArticleTitleThe structure of neuromelanin and its iron binding site studied by infrared spectroscopy FEBS Lett 457 18–22 Occurrence Handle10.1016/S0014-5793(99)01001-7 Occurrence Handle10486555 Occurrence Handle1:CAS:528:DyaK1MXmtFejsL4%3D

    Article  PubMed  CAS  Google Scholar 

  • JP Crow (1997) ArticleTitleDichlorodihydrofluorescein and dihydrorhodamine 123 are sensitive indicators of peroxynitrite in vivo: implications for intracellular measurement of reactive nitrogen and oxygen species Nitric Oxide 1 145–157 Occurrence Handle10.1006/niox.1996.0113 Occurrence Handle9701053 Occurrence Handle1:CAS:528:DyaK2sXislGktr0%3D

    Article  PubMed  CAS  Google Scholar 

  • RJ D’Amato ZP Lipman SH Snyder (1986) ArticleTitleSelectivity of the Parkinson neurotoxin, MPTP, toxic metabolite MPP+ binds to neuromelanin Science 231 987–989 Occurrence Handle3080808 Occurrence Handle1:CAS:528:DyaL28Xht1eisb4%3D

    PubMed  CAS  Google Scholar 

  • S Desagher A Osen-Sand A Nichols R Eskes S Montessuit S Lauper K Maundrell B Antonsson J-C Martinou (1999) ArticleTitleBid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis J Cell Biol 144 891–901 Occurrence Handle10.1083/jcb.144.5.891 Occurrence Handle10085289 Occurrence Handle1:CAS:528:DyaK1MXhs1yqtbY%3D

    Article  PubMed  CAS  Google Scholar 

  • KL Double P Riederer M Gerlach (1999) ArticleTitleThe significance of neuromelanin for neurodegeneration in Parkinson’s disease Drug News Perspect 12 333–340 Occurrence Handle1:CAS:528:DyaK1MXlvVagtLg%3D

    CAS  Google Scholar 

  • KL Double L Zecca P Costi M Mauer C Griesinger S Ito D Ben-Shachar G Bringmann RG Fariello P Riederer M Gerlach (2000) ArticleTitleStructural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins J Neurochem 75 2583–2589 Occurrence Handle10.1046/j.1471-4159.2000.0752583.x Occurrence Handle11080212 Occurrence Handle1:CAS:528:DC%2BD3cXotFKntrc%3D

    Article  PubMed  CAS  Google Scholar 

  • KL Double D Ben-Shachar MBH Youdim L Zecca P Riederer M Gerlach (2002) ArticleTitleInfluence of neuromelanin on oxidative pathways within the human substantia nigra Neurotoxicol Teratol 24 621–628 Occurrence Handle10.1016/S0892-0362(02)00218-0 Occurrence Handle12200193 Occurrence Handle1:CAS:528:DC%2BD38XmsVCit7o%3D

    Article  PubMed  CAS  Google Scholar 

  • KL Double M Gerlach V Schünemann AX Trautwein L Zecca M Gallorini MBH Youdim P Riederer D Ben-Shachar (2003) ArticleTitleIron binding characteristics of neuromelanin of the human substantia nigra Biochem Pharmacol 66 489–494 Occurrence Handle10.1016/S0006-2952(03)00293-4 Occurrence Handle12907248 Occurrence Handle1:CAS:528:DC%2BD3sXlvFygt70%3D

    Article  PubMed  CAS  Google Scholar 

  • A Dzierzega-Lecznar S Kurkiewicz E Chodurek K Stepien T Wilczok A Arzberger P Riederer M Gerlach (2004) ArticleTitleNeuromelanin of the human substantia nigra: structural investigations by pyrolysis-gas chromatography/mass spectrometry J Am Soc Mass Spectrometry 15 920–926 Occurrence Handle10.1016/j.jasms.2004.03.009 Occurrence Handle1:CAS:528:DC%2BD2cXktVOgtLg%3D

    Article  CAS  Google Scholar 

  • A Eckert B Steiner C Marques S Leutz H Roming C Haass WE Muller (2001) ArticleTitleElevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation J Neurosci Res 64 183–192 Occurrence Handle10.1002/jnr.1064 Occurrence Handle11288146 Occurrence Handle1:CAS:528:DC%2BD3MXislWnu7w%3D

    Article  PubMed  CAS  Google Scholar 

  • SL Elfering TM Sarkela C Giulivi (2002) ArticleTitleBiochemistry of mitochondrial nitric-oxide synthase J Biol Chem 277 38079–38086 Occurrence Handle10.1074/jbc.M205256200 Occurrence Handle12154090 Occurrence Handle1:CAS:528:DC%2BD38Xns1Cgurg%3D

    Article  PubMed  CAS  Google Scholar 

  • H Fedorow R Pickford JM Hook KL Double GM Halliday M Gerlach P Riederer B Garner (2005a) ArticleTitleDolichol is the major lipid component of human substantia nigra neuromelanin J Neurochem 92 990–995 Occurrence Handle10.1111/j.1471-4159.2004.02975.x Occurrence Handle1:CAS:528:DC%2BD2MXhs1Kqtbc%3D

    Article  CAS  Google Scholar 

  • H Fedorow F Tribl G Halliday M Gerlach P Riederer K Double (2005b) ArticleTitleNeuromelanin in human dopamine neurons: comparison with pheripheral melanins and relevance to Parkinson’s disease Progr Neurobiol 75 109–124 Occurrence Handle10.1016/j.pneurobio.2005.02.001 Occurrence Handle1:CAS:528:DC%2BD2MXisFKjsb8%3D

    Article  CAS  Google Scholar 

  • WP Gai HX Yuan XQ Li JT Power PH Jensen (2000) ArticleTitleIn situ and in vitro study of colocalization and segregation of α-synuclein, ubiquitin, and lipids in Lewy bodies Exp Neurol 166 324–333 Occurrence Handle10.1006/exnr.2000.7527 Occurrence Handle11085897 Occurrence Handle1:CAS:528:DC%2BD3cXotFCrsbo%3D

    Article  PubMed  CAS  Google Scholar 

  • M Gerlach AX Trautwein L Zecca MBH Youdim P Riederer (1995) ArticleTitleMoessbauer spectroscopic studies of purified neuromelanin isolated from the substantia nigra J Neurochem 65 923–926 Occurrence Handle7616255 Occurrence Handle1:CAS:528:DyaK2MXntFGgtL0%3D

    PubMed  CAS  Google Scholar 

  • B Halliwell (1992) ArticleTitleReactive oxygen species and the central nervous system J Neurochem 59 1609–1623 Occurrence Handle1402908 Occurrence Handle1:CAS:528:DyaK38XmsVKlsbk%3D

    PubMed  CAS  Google Scholar 

  • E Hirsch A Graybiel Y Agid (1988) ArticleTitleMelanized dopamine neurons are differentially susceptible to degeneration in Parkinson’s disease Nature 334 345–348 Occurrence Handle10.1038/334345a0 Occurrence Handle2899295 Occurrence Handle1:CAS:528:DyaL1cXltVyms78%3D

    Article  PubMed  CAS  Google Scholar 

  • K Ii H Ito K Tanaka A Hirano (1997) ArticleTitleImmunochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly J Neuropathol Exp Neurol 56 125–131 Occurrence Handle9034365 Occurrence Handle1:STN:280:ByiC1cnnsFQ%3D

    PubMed  CAS  Google Scholar 

  • A Kastner EC Hirsch O Lejeune F Javoy-Agid O Rascol Y Agid (1992) ArticleTitleIs the vulnerability of neurons in the substantia nigra of patients with Parkinson’s disease related to their neuromelanin contents? J Neurochem 59 1080–1089 Occurrence Handle1494900 Occurrence Handle1:CAS:528:DyaK38XlsVyms7Y%3D

    PubMed  CAS  Google Scholar 

  • E Leroy R Boyer G Auburger B Leube G Ulm E Mezey G Harta MJ Brownstein S Jonnalagada T Chernova A Dehejia G Iavadam T Gasser PJ Steinbach KD Wilkinson MH Polymeropoulos (1998) ArticleTitleThe ubiquitin pathway in Parkinson’s disease Nature 395 451–452 Occurrence Handle10.1038/26652 Occurrence Handle9774100 Occurrence Handle1:CAS:528:DyaK1cXms1antLo%3D

    Article  PubMed  CAS  Google Scholar 

  • L Lopiano D Digilio M Fasano S Giraudo M Rizzone E Torre B Bergamasco (1999) ArticleTitleIron and neuromelanin in Parkinson’s disease J Neural Transm 106 XXIV

    Google Scholar 

  • W Maruyama Y Kato T Yamamoto K Oh-hashi Y Hashizume M Naoi (2001) ArticleTitlePeroxynitrite induces neuronal cell death in aging and age-associated disorders J Am Aging Assoc 24 11–18 Occurrence Handle1:CAS:528:DC%2BD3MXltFeku70%3D

    CAS  Google Scholar 

  • KS McNaught LM Bjorklund R Belizaire O Isacson P Jenner CW Olanow (2002a) ArticleTitleProteasome inhibition causes nigral degeneration with inclusion bodies in rats Neuroreport 13 1437–1441 Occurrence Handle10.1097/00001756-200208070-00018 Occurrence Handle1:CAS:528:DC%2BD38Xmslaqur4%3D

    Article  CAS  Google Scholar 

  • KS McNaught P Shashidharam DP Perl P Jenner CW Olanow (2002b) ArticleTitleAggresome-related biogenesis of Lewy bodies Eur J Neurosci 16 2136–2148 Occurrence Handle10.1046/j.1460-9568.2002.02301.x

    Article  Google Scholar 

  • JS McNaught R Belizaire O Isacson P Jenner CW Olanow (2003a) ArticleTitleAltered proteasomal function in sporadic Parkinson’s disease Exp Neurol 179 38–46 Occurrence Handle10.1006/exnr.2002.8050 Occurrence Handle1:CAS:528:DC%2BD38Xps12ku70%3D

    Article  CAS  Google Scholar 

  • KS McNaught CW Olanow (2003b) ArticleTitleProteolytic stress: a unifying concept for the etiopathogenesis of Parkinson’s disease Ann Neurol 53 IssueID[Suppl 3] S73–S86 Occurrence Handle10.1002/ana.10512 Occurrence Handle1:CAS:528:DC%2BD3sXjtFGitLc%3D

    Article  CAS  Google Scholar 

  • TP Misco RJ Schilling D Salvemini WM Moore MG Currie (1993) ArticleTitleA fluorometric assay for the measurement of nitrite in biological samples Anal Biochem 214 11–16 Occurrence Handle10.1006/abio.1993.1449

    Article  Google Scholar 

  • M Naoi W Maruyama P Dostert (1994) ArticleTitleBinding of 1,2(N)-dimethyl-6,7-dihydroxy-isoquinolinium ion to melanin: effects of ferrous and ferric ion on the binding Neurosci Lett 171 9–12 Occurrence Handle10.1016/0304-3940(94)90591-6 Occurrence Handle8084506 Occurrence Handle1:CAS:528:DyaK2MXhtVegsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • G Odh R Garstam J Paulsin A Wittbjer E Rosengren H Rorsman (1994) ArticleTitleNeuromelanin of the human substantia nigra: a mixed-type melanin J Neurochem 62 2030–2036 Occurrence Handle8158151 Occurrence Handle1:CAS:528:DyaK2cXksl2is7o%3D

    PubMed  CAS  Google Scholar 

  • D Offen I Ziv A Barzilai S Gorodin E Glater A Hochman E Melamed (1997) ArticleTitleDopamine-melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson’s disease Neurochem Int 31 207–216 Occurrence Handle10.1016/S0197-0186(96)00150-7 Occurrence Handle9220453 Occurrence Handle1:CAS:528:DyaK2sXksFahs7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • M Shamoto-Nagai W Maruyama Y Kato K Isobe M Tanaka M Naoi T Osawa (2003) ArticleTitleAn inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells J Neurosci Res 74 589–597 Occurrence Handle10.1002/jnr.10777 Occurrence Handle14598303 Occurrence Handle1:CAS:528:DC%2BD3sXovVyhtL4%3D

    Article  PubMed  CAS  Google Scholar 

  • M Shamoto-Nagai W Maruyama Y Akao T Osawa F Tribl M Gerlach FA Zucca L Zecca P Riederer M Naoi (2004) ArticleTitleNeuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells J Neural Transm 111 1253–1265 Occurrence Handle10.1007/s00702-004-0211-2 Occurrence Handle15480837 Occurrence Handle1:CAS:528:DC%2BD2cXotFCrur0%3D

    Article  PubMed  CAS  Google Scholar 

  • T Shima T Sarna HM Swartz A Stroppolo R Gerbasi L Zecca (1997) ArticleTitleBinding of iron to neuromelanin of human substantia nigra and synthetic melanin: an electron paramagnetic resonance spectroscopy study Free Radic Biol Med 23 110–119 Occurrence Handle10.1016/S0891-5849(96)00623-5 Occurrence Handle9165303 Occurrence Handle1:CAS:528:DyaK2sXjtlarur8%3D

    Article  PubMed  CAS  Google Scholar 

  • D Sulzer J Bogulavsky KE Larsen G Behr E Karatekin MH Kleinman N Turro D Krantz RH Edwards LA Greene L Zecca (2000) ArticleTitleNeuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles Proc Natl Acad Sci USA 97 11869–11874 Occurrence Handle10.1073/pnas.97.22.11869 Occurrence Handle11050221 Occurrence Handle1:CAS:528:DC%2BD3cXnvVSgsLo%3D

    Article  PubMed  CAS  Google Scholar 

  • F Tribl M Gerlach K Marcus E Asan T Tatschner T Arzberger HE Meyer G Bringmann P Riederer (2005) ArticleTitle“Subcellular Proteomics” of neuromelanin granules isolated from the human brain Mol Cell Proteomics 4 945–957 Occurrence Handle10.1074/mcp.M400117-MCP200 Occurrence Handle15851778 Occurrence Handle1:CAS:528:DC%2BD2MXmtFKkurw%3D

    Article  PubMed  CAS  Google Scholar 

  • H Wilms P Rosenstiel J Sievers G Deuschl L Zecca R Lucius (2003) ArticleTitleActivation of microglia by human neuromelanin is NF-κB-dependent and involves p38 mitogen-activated protein kinase: implications for Parkinson’s disease FASEB J 10 IssueID17 500–502

    Google Scholar 

  • MB Youdim D Ben-Shachar P Riederer (1994) ArticleTitleThe enigma of neuromelanin in Parkinson’s disease substantia nigra J Neural Transm [Suppl] 43 113–122 Occurrence Handle1:STN:280:ByqC1M%2Fksl0%3D

    CAS  Google Scholar 

  • L Zecca R Pietra C Goj C Mecacci D Radice E Sabbioni (1994) ArticleTitleIron and other metals in neuromelanin, substantia nigra and putamen of human brain J Neurochem 62 1097–1100 Occurrence Handle8113797 Occurrence Handle1:CAS:528:DyaK2cXhvVOrtr8%3D

    PubMed  CAS  Google Scholar 

  • L Zecca P Costi C Meccaci S Ito T Terreni S Sonnino (2000) ArticleTitleThe interaction of human substantia nigra neuromelanin with lipids and peptides J Neurochem 74 1758–1765 Occurrence Handle10.1046/j.1471-4159.2000.0741758.x Occurrence Handle10737635 Occurrence Handle1:CAS:528:DC%2BD3cXitVens70%3D

    Article  PubMed  CAS  Google Scholar 

  • L Zecca D Tampellini A Gatti R Crippa M Eisner D Sulzer S Ito R Fariello M Gallorini (2002) ArticleTitleThe neuromelanin of human substantia nigra and its interaction with metals J Neural Transm 109 663–672 Occurrence Handle10.1007/s007020200055 Occurrence Handle12111458 Occurrence Handle1:CAS:528:DC%2BD38XmtVCqs7s%3D

    Article  PubMed  CAS  Google Scholar 

  • F Zhang G Dryhurst (1994) ArticleTitleEffects of L-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to idiopathic Parkinson’s disease J Med Chem 37 1084–1096 Occurrence Handle10.1021/jm00034a006 Occurrence Handle7909337 Occurrence Handle1:CAS:528:DyaK2cXisVWksLs%3D

    Article  PubMed  CAS  Google Scholar 

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Affiliations

  1. Department of Geriatric Medicine, National Institute for Geriatrics and Gerontology, Obu, Aichi, Japan

    M. Shamoto-Nagai & W. Maruyama

  2. Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan

    H. Yi, Y. Akao & M. Naoi

  3. Department of Psychiatry and Psychotherapy, Clinical Neurochemistry and NPF Center of Excellence Laboratories, Würzburg, Germany

    F. Tribl & P. Riederer

  4. Laboratory of Clinical Neurochemistry, Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    M. Gerlach

  5. Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya, Aichi, Japan

    T. Osawa

Authors
  1. M. Shamoto-Nagai
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  2. W. Maruyama
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  3. H. Yi
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  4. Y. Akao
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  5. F. Tribl
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  6. M. Gerlach
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  7. T. Osawa
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  8. P. Riederer
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  9. M. Naoi
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Shamoto-Nagai, M., Maruyama, W., Yi, H. et al. Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome. J Neural Transm 113, 633–644 (2006). https://doi.org/10.1007/s00702-005-0410-5

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  • DOI: https://doi.org/10.1007/s00702-005-0410-5

  • Keywords: Neuromelanin, mitochondria, oxidative stress, Parkinson’s disease, ubiquitin-proteasome system, ferrous iron.