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The role of metal ions in dopaminergic neuron degeneration in Parkinsonism and Parkinson’s disease

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Abstract

Parkinson’s disease is characterized by the selective degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra and locus coeruleus. Although the cause of this disease remains unknown, several transition metals, including manganese and copper, have been associated with the development of the atypical form of Parkinsonism, and iron accumulation has been associated with the development of Parkinson’s disease. Manganese3+ is a strong oxidizing agent, which oxidizes dopamine to aminochrome (dopaminochrome), the precursor of neuromelanin. Aminochrome formation in cell culture medium induces acute cell death in cells that uptake aminochrome, explaining the role of manganese in the development of atypical Parkinsonism. Copper accumulation in Wilson’s disease also induces Parkinsonism as one of the main symptoms, and an atypical Parkinsonism has also been observed in young copper miners. Interestingly, copper is able to complex with dopamine, which can be taken up by cells expressing the dopamine transporter, inducing caspase-independent cell death with formation of autophagic vacuoles. Iron is also able to form a complex with dopamine, the neurotoxic action of which also depends on the cellular expression of the dopamine transporter. The neurotoxicities of these transition metals to cells expressing the dopamine transporter all involve dopamine oxidation to quinones and require the inhibition of DT-diaphorase.

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References

  1. HaMai D, Bondy SC (2004) Ann N Y Acad Sci 1012:129

    Article  CAS  Google Scholar 

  2. Sriram K, Lin GX, Jefferson AM, Roberts JR, Chapman RS, Chen BT, Soukup JM, Ghio AJ, Antonini JM (2010) Arch Toxicol 84:521

    Article  CAS  Google Scholar 

  3. Settivari R, Levora J, Nass R (2009) J Biol Chem 284:35758

    Article  CAS  Google Scholar 

  4. Zhang P, Lokuta KM, Turner DE, Liu B (2010) J Neurochem 112:434

    Article  CAS  Google Scholar 

  5. Zhang P, Wong TA, Lokuta KM, Turner DE, Vujisic K, Liu B (2009) Exp Neurol 217:219

    Article  CAS  Google Scholar 

  6. Moreno JA, Streifel KM, Sullivan KA, Legare ME, Tjalkens RB (2009) Toxicol Sci 112:405

    Article  CAS  Google Scholar 

  7. Zhao F, Cai T, Liu M, Zheng G, Luo W, Chen J (2009) Toxicol Sci 107:156

    Article  CAS  Google Scholar 

  8. Posser T, Franco JL, Bobrovskaya L, Leal RB, Dickson PW, Dunkley PR (2009) J Neurochem 110:848

    Article  CAS  Google Scholar 

  9. Stanwood GD, Leitch DB, Savchenko V, Wu J, Fitsanakis VA, Anderson DJ, Stankowski JN, Aschner M, McLaughlin B (2009) J Neurochem 110:378

    Article  CAS  Google Scholar 

  10. Prabhakaran K, Ghosh D, Chapman GD, Gunasekar PG (2008) Brain Res Bull 76:361

    Article  CAS  Google Scholar 

  11. Anderson JG, Cooney PT, Erikson KM (2007) Environ Toxicol Pharmacol 3:179

    Article  Google Scholar 

  12. McDougall SA, Reichel CM, Farley CM, Flesher MM, Der-Ghazarian T, Cortez AM, Wacan JJ, Martinez CE, Varela FA, Butt AE, Crawford CA (2008) Neuroscience 154:848

    Article  CAS  Google Scholar 

  13. Hirata Y, Suzuno H, Tsuruta T, Oh-hashi K, Kiuchi K (2008) Toxicology 244:249

    Article  CAS  Google Scholar 

  14. Williams BB, Kwakye GF, Wegrzynowicz M, Li D, Aschner M, Erikson KM, Bowman AB (2010) Toxicol Sci 117:169

    Article  CAS  Google Scholar 

  15. Hirsch EC (2009) Parkinsonism Relat Disord 15:S209

    Article  Google Scholar 

  16. Du T, Ciccotosto GD, Cranston GA, Kocak G, Masters CL, Crouch PJ, Cappai R, White AR (2008) Free Radic Biol Med 44:44

    Article  CAS  Google Scholar 

  17. Zhang S, Wang J, Song N, Xie J, Jiang H (2009) Neurobiol Aging 30:1466

    Article  CAS  Google Scholar 

  18. Huang E, Ong WY, Go ML, Connor JR (2006) Exp Brain Res 170:376

    Article  CAS  Google Scholar 

  19. Huang E, Ong WY, Connor JR (2004) Neuroscience 128:487

    Article  CAS  Google Scholar 

  20. Aguirre P, Mena N, Tapia V, Arredondo M, Núñez MT (2005) BMC Neurosci 6:3

    Article  Google Scholar 

  21. Lis A, Barone TA, Paradkar PN, Plunkett RJ, Roth JA (2004) Brain Res Mol Brain Res 122:62

    Article  CAS  Google Scholar 

  22. Knutson M, Menzies S, Connor J (2004) J Neurosci Res 76:633

    Article  CAS  Google Scholar 

  23. Wang XS, Ong WY, Connor JR (2003) 120:21

  24. Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ (2001) J Neurosci Res 66:1198

    Article  CAS  Google Scholar 

  25. Perl DP, Olanow CW (2007) J Neuropathol Exp Neurol 66:675

    Article  CAS  Google Scholar 

  26. Donaldson J, LaBella FS, Gesser D (1981) Neurotoxicology 2:53

    CAS  Google Scholar 

  27. Archibald FS, Tyree C (1987) Arch Biochem Biophys 256:638

    Article  CAS  Google Scholar 

  28. Segura-Aguilar J, Lind C (1989) Chem Biol Interact 72:309

    Article  CAS  Google Scholar 

  29. Stredrick DL, Stokes AH, Worst TJ, Freeman WM, Johnson EA, Lash LH

  30. Eriksson H, Heilbronn E (1983) Arch Toxicol 54:53

    Article  CAS  Google Scholar 

  31. Cai T, Yao T, Li Y, Chen Y, Du K, Chen J, Luo W (2007) Brain Res 1185:359

    Article  CAS  Google Scholar 

  32. Arriagada C, Paris I, Sanchez de las Matas MJ, Martinez-Alvarado P, Cardenas S, Castañeda P, Graumann R, Perez-Pastene C, Olea-Azar C, Couve E, Herrero MT, Caviedes P, Segura-Aguilar J (2004) Neurobiol Dis 16:468

    Article  CAS  Google Scholar 

  33. Segura-Aguilar J, Metodiewa D, Baez S (2001) Neurotox Res 3:157

    Article  CAS  Google Scholar 

  34. Paris I, Dagnino-Subiabre A, Marcelain K, Bennett LB, Caviedes P, Caviedes R, Azar CO, Segura-Aguilar J (2001) J Neurochem 77:519

    Article  CAS  Google Scholar 

  35. Paris I, Martinez-Alvarado P, Perez-Pastene C, Vieira MN, Olea-Azar C, Raisman-Vozari R, Cardenas S, Graumann R, Caviedes P, Segura-Aguilar J (2005) J Neurochem 92:1021

    Article  CAS  Google Scholar 

  36. Paris I, Cardenas S, Lozano J, Perez-Pastene C, Graumann R, Riveros A, Caviedes P, Segura-Aguilar J (2007) Neurotox Res 12:125

    Article  CAS  Google Scholar 

  37. Paris I, Lozano J, Perez-Pastene C, Muñoz P, Segura-Aguilar J (2009) Neurotox Res 16:271

    Article  CAS  Google Scholar 

  38. Paris I, Perez-Pastene C, Cardenas S, Iturriaga-Vasquez P, Muñoz P, Couve E, Caviedes P, Segura-Aguilar J (2010) Neurotox Res 18:82

    Article  Google Scholar 

  39. Paris I, Perez-Pastene C, Couve E, Caviedes P, Ledoux S, Segura-Aguilar J (2009) J Biol Chem 284:13306

    Article  CAS  Google Scholar 

  40. Fuentes P, Paris I, Nassif M, Caviedes P, Segura-Aguilar J (2007) Chem Res Toxicol 20:776

    Article  CAS  Google Scholar 

  41. Segura-Aguilar J, Diaz-Veliz G, Mora S, Herrera-Marschitz M (2002) Neurotox Res 4:127

    Article  CAS  Google Scholar 

  42. Paris I, Lozano J, Cardenas S, Perez-Pastene C, Saud K, Fuentes P, Caviedes P, Dagnino-Subiabre A, Raisman-Vozari R, Shimahara T, Kostrzewa JP, Chi D, Kostrzewa RM, Caviedes R, Segura-Aguilar J (2008) Neurotox Res 13:221

    Article  CAS  Google Scholar 

  43. Díaz-Véliz G, Mora S, Gómez P, Dossi MT, Montiel J, Arriagada C, Aboitiz F, Segura-Aguilar J (2004) Pharmacol Biochem Behav 77:245

    Article  Google Scholar 

  44. Díaz-Véliz G, Mora S, Dossi MT, Gómez P, Arriagada C, Montiel J, Aboitiz F, Segura-Aguilar J (2002) Pharmacol Biochem Behav 73:843

    Article  Google Scholar 

  45. Strausak D, Mercer JF, Dieter HH, Stremmel W, Multhaup G (2001) Brain Res Bull 55:175

    Article  CAS  Google Scholar 

  46. Du F, Qian ZM, Zhu L, Wu XM, Yung WH, Tsim TY, Ke Y (2009) PLoS One 4:e4593

    Article  Google Scholar 

  47. White AR, Cappai R (2003) J Neurosci Res 71:889

    Article  CAS  Google Scholar 

  48. Reddy PV, Rao KV, Norenberg MD (2008) Lab Invest 88:816

    Article  CAS  Google Scholar 

  49. Lu J, Zheng YL, Wu DM, Sun DX, Shan Q, Fan SH (2006) FEBS Lett 580:6730

    Article  CAS  Google Scholar 

  50. Lu J, Wu DM, Zheng YL, Sun DX, Hu B, Shan Q, Zhang ZF, Fan SH (2009) Brain Behav Immun 23:193

    Article  CAS  Google Scholar 

  51. Zheng Z, White C, Lee J, Peterson TS, Bush AI, Sun GY, Weisman GA, Petris MJ (2010) J Neurochem 114:1630

    Article  CAS  Google Scholar 

  52. Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR (2007) Medicine (Baltimore) 86:112

    Article  Google Scholar 

  53. Caviedes P, Segura-Aguilar J (2001) Neuroreport 12:A25

    Article  Google Scholar 

  54. Segura-Aguilar J, Metodiewa D, Welch CJ (1998) Biochim Biophys Acta 1381:1

    CAS  Google Scholar 

  55. Díaz-Véliz G, Paris I, Mora S, Raisman-Vozari R, Segura-Aguilar J (2008) Chem Res Toxicol 21:1180

    Article  Google Scholar 

  56. Wimalasena DS, Wiese TJ, Wimalasena K (2009) J Neurochem 101:313

    Article  Google Scholar 

  57. Kume A, Shiratori M, Takahashi A, Kato T, Ito K, Tadokoro M, Sakuma S (1992) J Neurol Sci 110:37

    Article  CAS  Google Scholar 

  58. Zhang J, Zhang Y, Wang J, Cai P, Luo C, Qian Z, Dai Y, Feng H (2010) Brain Res 1330:124

    Article  CAS  Google Scholar 

  59. Song N, Jiang H, Wang J, Xie JX (2007) J Neurosci Res 85:3118

    Article  CAS  Google Scholar 

  60. Roth JA, Singleton S, Feng J, Garrick M, Paradkar PN (2010) J Neurochem 113:454

    Article  CAS  Google Scholar 

  61. Hirsch EC (2009) Parkinsonism Relat Disord 15:S209

    Article  Google Scholar 

  62. Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nuñez MT, Garrick MD, Raisman-Vozari R, Hirsch EC (2008) Proc Natl Acad Sci USA 105:18578

    Article  CAS  Google Scholar 

  63. Wang J, Jiang H, Xie JX (2007) Eur J Neurosci 25:2766

    Article  Google Scholar 

  64. Song N, Wang J, Jiang H, Xie J (2010) Free Radic Biol Med 48:332

    Article  CAS  Google Scholar 

  65. Zhu W, Li X, Xie W, Luo F, Kaur D, Andersen JK, Jankovic J, Le W (2010) Neurobiol Dis 37:307

    Article  Google Scholar 

  66. Kaur D, Lee D, Ragapolan S, Andersen JK (2009) Free Radic Biol Med 46:593

    Article  CAS  Google Scholar 

  67. Tribl F, Asan E, Arzberger T, Tatschner T, Langenfeld E, Meyer HE, Bringmann G, Riederer P, Gerlach M, Marcus K (2009) Mol Cell Proteomics 8:1832

    Article  CAS  Google Scholar 

  68. Youdim MB, Grünblatt E, Mandel S (2007) J Neural Transm 114:205

    Article  CAS  Google Scholar 

  69. Xu Q, Kanthasamy AG, Reddy MB (2008) Toxicology 245:101

    Article  CAS  Google Scholar 

  70. Maharaj DS, Maharaj H, Daya S, Glass BD (2006) J Neurochem 96:78

    Article  CAS  Google Scholar 

  71. Wang R, Qing H, Liu XQ, Zheng XL, Deng YL (2008) Neurosci Bull 24:125

    Article  CAS  Google Scholar 

  72. Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T (2008) J Neurochem 106:1866

    CAS  Google Scholar 

  73. Double KL, Halliday GM, Henderson J, Griffiths FM, Heinemann T, Riederer P, Gerlach M (2003) Exp Neurol 184:530

    Article  CAS  Google Scholar 

  74. Paris I, Martinez-Alvarado P, Cárdenas S, Perez-Pastene C, Graumann R, Fuentes P, Olea-Azar C, Caviedes P, Segura-Aguilar J (2005) Chem Res Toxicol 18:415

    Article  CAS  Google Scholar 

  75. Arreguin S, Nelson P, Padway S, Shirazi M, Pierpont C (2009) J Inorg Biochem 103:87

    Article  CAS  Google Scholar 

  76. Siraki AG, Smythies J, O’Brien PJ (2000) Neurosci Lett 296:37

    Article  CAS  Google Scholar 

  77. Ortega R, Cloetens P, Devès G, Carmona A, Bohic S (2007) PLoS One 2:e925

    Article  Google Scholar 

  78. Mohamed GG, Zayed MA, El-Dien FA, El-Nahas RG (2004) Spectrochim Acta A 60:1775

    Article  Google Scholar 

  79. Arriagada C, Dagnino-Subiabre A, Caviedes P, Armero JM, Caviedes R, Segura-Aguilar J (2000) Amino Acids 18:363

    Article  CAS  Google Scholar 

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Acknowledgments

Supported by FONDECYT 1100165.

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Authors and Affiliations

  1. Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, Independencia 1027, 70000, Casilla, Santiago, Chile

    Irmgard Paris & Juan Segura-Aguilar

  2. University of Santo Tomás, Viña del Mar, Chile

    Irmgard Paris

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  1. Irmgard Paris
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  2. Juan Segura-Aguilar
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Correspondence to Juan Segura-Aguilar.

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Paris, I., Segura-Aguilar, J. The role of metal ions in dopaminergic neuron degeneration in Parkinsonism and Parkinson’s disease. Monatsh Chem 142, 365–374 (2011). https://doi.org/10.1007/s00706-011-0478-6

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  • DOI: https://doi.org/10.1007/s00706-011-0478-6

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