Skip to main content
SpringerLink
Log in

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

  • Chapter
  • First Online:
Toxicity and Autophagy in Neurodegenerative Disorders

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 9))

Abstract

Four decades after L-dopa was introduced as a therapy for Parkinson’s disease, it is still the gold standard for Parkinson’s pharmacological treatment because no new drug has been discovered. This is due to the ambiguity regarding the molecular mechanisms responsible for the degeneration of dopaminergic neurons containing neuromelanin in the substantia nigra, which induces the motor symptoms of Parkinson’s disease. The question is to identify the mechanisms underlying the neurodegenerative process of Parkinson’s disease initiated years before the motor symptoms are evident, through pre-motor symptoms. The possible role of an exogenous environmental neurotoxin has been proposed. However, MPTP generates severe Parkinsonism in just 3 days, in contrast with idiopathic Parkinson’s disease, which occurs after years of slow degeneration. The discovery of proteins (such as alpha synuclein and parkin) associated with the familial form of the disease opened new lines of basic research, resulting in a general agreement that five mechanisms are involved in the degeneration of dopaminergic neurons containing neuromelanin: protein degradation dysfunction, mitochondrial dysfunction, alpha synuclein aggregation, oxidative stress and neuroinflammation. Dopamine oxidation sequentially generates dopamine o-quinone, aminochrome, 5,6-indolequinone and finally, neuromelanin. These o-quinones have been reported to be directly involved in four of the five above-mentioned mechanisms: protein degradation dysfunction, mitochondria dysfunction, alpha synuclein aggregation and oxidative stress. This suggests that dopamine oxidation to o-quinone may play a role in the degeneration of the dopaminergic neurons of the nigrostriatal system in Parkinson’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AADC:

Aromatic amino acid decarboxylase

TH:

Tyrosine hydroxylase

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

VMAT-2:

Vesicular monoaminergic transporter-2

DAT:

Dopamine transporter

MAO:

Monoamine oxidase

COMT:

Catechol ortho-methyltransferase

UCHL-1:

Ubiquitin carboxyl-terminal hydrolase isozyme

GSTM2:

Glutathione S-transferase M2-2

ATP13A2:

ATPase type 13 A

PINK1:

PTEN-induced kinase 1

LRRK-2:

Leucine-rich repeat kinase 2

DJ-1:

Parkinson protein 7

References

  1. Eser BE, Fitzpatrick PF. Measurement of intrinsic rate constants in the tyrosine hydroxylase reaction. BioChemistry. 2010;49:645–52.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Nagatsu T. Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. Essays Biochem. 1995;30:15–35.

    CAS  PubMed  Google Scholar 

  3. Cartier EA, Parra LA, Baust TB, Quiroz M, Salazar G, Faundez V, Egaña L, Torres GE. A biochemical and functional protein complex involving dopamine synthesis and transport into synaptic vesicles. J Biol Chem. 2010;151:957–66.

    Google Scholar 

  4. Linert W, Herlinger E, Jameson RF, Kienzl E, Jellinger K, Youdim MB. Dopamine, 6-hydroxydopamine, iron, and dioxygen–their mutual interactions and possible implication in the development of Parkinson’s disease. Biochim Biophys Acta. 1996;1316:160–8.

    PubMed  Google Scholar 

  5. Guillot TS, Miller GW. Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons. Mol Neurobiol. 2009;39:149–70.

    CAS  PubMed  Google Scholar 

  6. Fuentes P, Paris I, Nassif M, Cavies P, Segura-Aguilar J. Inhibition of VMAT-2 and DT-diaphorase induce cell death in a substantia nigra-derived cell line–an experimental cell model for dopamine toxicity studies. Chem Res Toxicol. 2007;20:776–83.

    CAS  PubMed  Google Scholar 

  7. Sulzer D, Bogulavsky J, Larsen KE, Behr G, Karatekin E, Kleinman MH, Turro N, Krantz D, Edwards RH, Greene LA, Zecca L. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci U S A. 2000;97:11869–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Liang CL, Nelson O, Yazdani U, Pasbakhsh P, German DC. Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J Comp Neurol. 2004;473:97–106.

    CAS  PubMed  Google Scholar 

  9. Eriksen J, Jørgensen TN, Gether U. Regulation of dopamine transporter function by protein-protein interactions: new discoveries and methodological challenges. J Neurochem. 2010;113:27–41.

    CAS  PubMed  Google Scholar 

  10. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996;379:606–12.

    CAS  PubMed  Google Scholar 

  11. Jones SR, Gainetdinov RR, Wightman RM, Caron MG. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci. 1998;18:1979–86.

    CAS  PubMed  Google Scholar 

  12. Bach AWJ, Lan NC, Johnson DL, Abell CW, Bemkenek ME, Kwan SW, Seeburg PH, Shih JC. cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci U S A. 1988;85:4934–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Weyler W, Hsu YP, Breakefield XO. Biochemistry and genetics of monoamine oxidase. Pharmacol Ther. 1990;47:391–417.

    CAS  PubMed  Google Scholar 

  14. Shih JC, Grimsby J, Chen K. Molecular biology of monoamine oxidase A and B: their role in the degradation of serotonin. In: Baumgarten HG, Gothert M, editors. Handbook of experimental pharmacology. Serotoninergic neurons and 5-HT receptors in the CNS. Vol. 129. Berlin: Springer-Verlag; 1997. pp. 655–70.

    Google Scholar 

  15. Westlund KN, Denney RM, Rose RM, Abell CW. Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem. Neuroscience. 1988;25:439–56.

    CAS  PubMed  Google Scholar 

  16. Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, Loffler J, Richards JG. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience. 1994;62:15–30.

    CAS  PubMed  Google Scholar 

  17. Shih JC. Molecular basis of human MAO A and B. Neuropsychopharmacology. 1991;4:1–7.

    CAS  PubMed  Google Scholar 

  18. Strolin-Benedetti M, Dostert P, Tipton KF. Developmental aspects of the monoamine-degrading enzyme monoamine oxidase. Dev Pharmacol Ther. 1992;18:191–200.

    CAS  PubMed  Google Scholar 

  19. Di Monte DA, Royland JE, Irwin I, Langston JW. Astrocytes as the site for bioactivation of neurotoxins. Neurotoxicol Fall-Winter. 1996;17:697–703.

    CAS  Google Scholar 

  20. Myöhänen TT, Schendzielorz N, Männistö PT. Distribution of catechol-O-methyltransferase (COMT) proteins and enzymatic activities in wild-type and soluble COMT deficient mice. J Neurochem. 2010;113:1632–43.

    PubMed  Google Scholar 

  21. 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. New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. Proc Natl Acad Sci U S A. 2008;105:17567–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Segura-Aguilar J, Lind C. On the mechanism of Mn3(+)-induced neurotoxicity of dopamine: prevention of quinone derived oxygen toxicity by DT-diaphorase and superoxide dismutase. Chem Biol Interact. 1989;72:309–24.

    CAS  PubMed  Google Scholar 

  23. Park RM. Neurobehavioral deficits and parkinsonism in occupations with manganese exposure: a review of methodological issues in the epidemiological literature. Saf Health Work. 2013;4:123–35.

    PubMed Central  PubMed  Google Scholar 

  24. Tuschl K, Mills PB, Clayton PT. Manganese and the brain. Int Rev Neurobiol. 2013;110:277–312.

    CAS  PubMed  Google Scholar 

  25. Fujishiro H, Ohashi T, Takuma M, Himeno S. Down-regulation of S100A9 and S100A10 in manganese-resistant RBL-2H3 cells. J Toxicol Sci. 2013;38:753–7.

    CAS  PubMed  Google Scholar 

  26. Caviedes P, Segura-Aguilar J. The price of development in Chile: overcoming environmental hazards produced by heavy industrial exploitation. Neuroreport. 2001;12:A25.

    Google Scholar 

  27. Paris I, Dagnino–Subiabre A, Marcelain K, Bennett LB, Caviedes P, Caviedes R, Olea-Azar C, Segura-Aguilar J. Copper neurotoxicity is dependent on dopamine-mediated copper uptake and one-electron reduction of aminochrome in a rat substantia nigra neuronal cell line. J Neurochem. 2001;77:519–29.

    CAS  PubMed  Google Scholar 

  28. Paris I, Perez-Pastene C, Couve E, Caviedes P, Ledoux S, Segura-Aguilar J. Copper dopamine complex induces mitochondrial autophagy preceding caspase-independent apoptotic cell death. J Biol Chem. 2009;284:13306–15.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore). 2007;86:112–21.

    Google Scholar 

  30. Przybyłkowski A, Gromadzka G, Członkowska A. Polymorphisms of metal transporter genes DMT1 and ATP7A in Wilson’s disease. J Trace Elem Med Biol. 2014;28:8–12.

    PubMed  Google Scholar 

  31. Zhou ZD, Lan YH, Tan EK, Lim TM. Iron species-mediated dopamine oxidation, proteasome inhibition, and dopaminergic cell demise: implications for iron-related dopaminergic neuron degeneration. Free Radic Biol Med. 2010;49:1856–71.

    CAS  PubMed  Google Scholar 

  32. Paris I, Martinez-Alvarado P, Cardenas S, Perez-Pastene C, Graumann R, Fuentes P, Olea-Azar C, Caviedes P, Segura-Aguilar J. Dopamine-dependent iron toxicity in cells derived from rat hypothalamus. Chem Res Toxicol. 2005;18:415–9.

    CAS  PubMed  Google Scholar 

  33. 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. Monoamine transporter inhibitors and norepinephrine reduce dopamine-dependent iron dependent iron toxicity in cells derived from the substantia nigra. J Neurochem. 2005;92:1021–32.

    CAS  PubMed  Google Scholar 

  34. Bisaglia M, Mammi S, Bubacco L. Kinetic and structural analysis of the early oxidation products of dopamine: analysis of the interactions with alpha-synuclein. J Biol Chem. 2007;282:15597–605.

    CAS  PubMed  Google Scholar 

  35. Jana S, Sinha M, Chanda D, Roy T, Banerjee K, Munshi S, Patro BS, Chakrabarti S. Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: implications in dopamine cytotoxicity and pathogenesis of Parkinson’s disease. Biochim Biophys Acta. 2011;1812:663–73.

    CAS  PubMed  Google Scholar 

  36. Jimenez M, Garcia-Carmona F, Garcia-Canovas F, Iborra JL, Lozano JA, Martinez F. Chemical intermediates in dopamine oxidation by tyrosinase, and kinetic studies of the process. Arch Biochem Biophys. 1984;235:438–48.

    CAS  PubMed  Google Scholar 

  37. Hastings TG. Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem. 1995;64:919–24.

    CAS  PubMed  Google Scholar 

  38. Foppoli C, Coccia R, Cini C, Rosei MA. Catecholamines oxidation by xanthine oxidase. Biochim Biophys Acta. 1997;1334:200–6.

    CAS  PubMed  Google Scholar 

  39. Segura-Aguilar J. Peroxidase activity of liver microsomal vitamin D 25-hydroxylase and cytochrome P450 1A2 catalyzes 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome. Biochem Mol Med. 1996;58:122–9.

    CAS  PubMed  Google Scholar 

  40. Galzigna L, De Iuliis A, Zanatta L. Enzymatic dopamine peroxidation in substantia nigra of human brain. Clin Chim Acta. 2000;300:131–8.

    CAS  PubMed  Google Scholar 

  41. Thompson M, Capdevila JH, Strobel HW. Recombinant cytochrome P450 2D18 metabolism of dopamine and arachidonic acid. J Pharmacol Exp Ther. 2000;294:1120–30.

    CAS  PubMed  Google Scholar 

  42. Segura-Aguilar J, Metodiewa D, Welch C. Metabolic activation of dopamine o-quinones to o-semiquinones by NADPH cytochrome P450 reductase may play an important role in oxidative stress and apoptotic effects. Biochim Biophys Acta. 1998;1381:1–6.

    CAS  PubMed  Google Scholar 

  43. Bisaglia M, Soriano ME, Arduini I, Mammi S, Bubacco L. Molecular characterization of dopamine-derived quinones reactivity toward NADH and glutathione: implications for mitochondrial dysfunction in Parkinson disease. Biochim Biophys Acta. 2010;1802:699–706.

    CAS  PubMed  Google Scholar 

  44. Tse DC, McCreery RL, Adams RN. Potential oxidative pathways of brain catecholamines. J Med Chem. 1976;19:37–40.

    CAS  PubMed  Google Scholar 

  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. Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson’s disease. J Neurochem. 2005;93:246–56.

    CAS  PubMed  Google Scholar 

  46. Napolitano A, Manini P, d’Ischia M. Oxidation chemistry of catecholamines and neuronal degeneration: an update. Curr Med Chem. 2011;18:1832–45.

    CAS  PubMed  Google Scholar 

  47. Bisaglia M, Tosatto L, Munari F, Tessari I, de Laureto PP, Mammi S, Bubacco L. Dopamine quinones interact with alpha-synuclein to form unstructured adducts. Biochem Biophys Res Commun. 2010;394:424–8.

    CAS  PubMed  Google Scholar 

  48. Hauser DN, Hastings TG. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis. 2013;51:35–42.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Van Laar VS, Mishizen AJ, Cascio M, Hastings TG. Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol Dis. 2009;34:487–500.

    PubMed Central  PubMed  Google Scholar 

  50. Van Laar VS, Dukes AA, Cascio M, Hastings TG. Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: implications for Parkinson disease. Neurobiol Dis. 2008;29:477–89.

    PubMed Central  PubMed  Google Scholar 

  51. Xu Y, Stokes AH, Roskoski R Jr, Vrana KE. Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase. J Neurosci Res. 1998;54:691–7.

    CAS  PubMed  Google Scholar 

  52. Whitehead RE, Ferrer JV, Javitch JA, Justice JB. Reaction of oxidized dopamine with endogenous cysteine residues in the human dopamine transporter. J Neurochem. 2001;76:1242–51.

    CAS  PubMed  Google Scholar 

  53. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ. Dopamine covalently modifies and functionally inactivates parkin. Nat Med. 2005;11:1159–61.

    Google Scholar 

  54. Arriagada A, Paris I, Sanchez de las Matas MJ, Martinez-Alvarado P, Cardenas S, Castaña P, Graumann R, Perez-Pastene C, Olea-Azar C, Couve E, Herrero MT, Caviedes P, Segura-Aguilar J. On the neurotoxicity of leukoaminochrome o-semiquinone radical derived of dopamine oxidation: mitochondria damage, necrosis and hydroxyl radical formation. Neurobiol Dis. 2004;16:468–77.

    CAS  PubMed  Google Scholar 

  55. Dagnino-Subiabre A, Cassels BK, Baez S, Johansson AS, Mannervik B, Segura-Aguilar J. Glutathione transferase M2-2 catalyzes conjugation of dopamine and dopa o-quinones. Biochem Biophys Res Commun. 2000;274:32–6.

    CAS  PubMed  Google Scholar 

  56. Lozano J, Muñoz P, Nore BF, Ledoux S, Segura-Aguilar J. Stable expression of short interfering RNA for DT-diaphorase induces neurotoxicity. Chem Res Toxicol. 2010;23:1492–6.

    CAS  PubMed  Google Scholar 

  57. Paris I, Muñoz P, Huenchuguala S, Couve E, Sanders LH, Greenamyre JT, Caviedes P, Segura-Aguilar J. Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line. Toxicol Sci. 2011;121:376–88.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Paris I, Perez-Pastene C, Cardenas S, Iturriaga-Vasquez P, Muñoz P, Couve E, Caviedes P, Segura-Aguilar J. Aminochrome induces disruption of actin, alpha-, and beta-tubulin cytoskeleton networks in substantia-nigra-derived cell line. Neurotox Res. 2010;18:82–92.

    PubMed  Google Scholar 

  59. Huenchuguala S, Muñoz P, Zavala P, Villa M, Cuevas C, Ahumada U, Graumann R, Nore BF, Couve E, Mannervik B, Paris I, Segura-Aguilar J. Glutathione transferase mu 2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction. Autophagy. 2014;10:618–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Aguirre P, Urrutia P, Tapia V, Villa M, Paris I, Segura-Aguilar J, Núñez MT. The dopamine metabolite aminochrome inhibits mitochondrial complex I and modifies the expression of iron transporters DMT1 and FPN1. Biometals. 2012;25:795–803.

    CAS  PubMed  Google Scholar 

  61. Muñoz P, Paris I, Sanders LH, Greenamyre JT, Segura-Aguilar J. Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-deriv cells against aminochrome neurotoxicity. Biochim Biophys Acta. 2012;1822:1125–36.

    PubMed  Google Scholar 

  62. Muñoz P, Huenchuguala S, Paris I, Cuevas C, Villa M, Cavies P, Segura-Aguilar J, Tizabi Y. Protective effects of nicotine against aminochrome-induced toxicity in substantia nigra derived cells: implications for Parkinson’s disease. Neurotox Res. 2012;22:177–80.

    PubMed Central  PubMed  Google Scholar 

  63. Segura-Aguilar J, Baez S, Widersten M, Welch CJ, Mannervik B. Human class Mu glutathione transferases, in particular isoenzyme M2-2, catalyze detoxication of the dopamine metabolite aminochrome. J Biol Chem. 1997;272:5727–31.

    CAS  PubMed  Google Scholar 

  64. Sulzer D, Mosharov E, Talloczy Z, Zucca FA, Simon JD, Zecca L. Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease. J Neurochem. 2008;106:24–36.

    CAS  PubMed  Google Scholar 

  65. Wakamatsu K, Fujikawa K, Zucca FA, Zecca L, Ito S. The structure of neuromelanin as studied by chemical degradative methods. J Neurochem. 2003;86:1015–23.

    CAS  PubMed  Google Scholar 

  66. Wakamatsu K, Murase T, Zucca FA, Zecca L, Ito S. Biosynthetic pathway to neuromelanin and its aging process. Pigment Cell Melanoma Res. 2012;25:792–803.

    CAS  PubMed  Google Scholar 

  67. Mattammal MB, Strong R, Lakshmi VM, Chung HD, Stephenson AH. Prostaglandin H synthetase–mediated metabolism of dopamine: implication for Parkinson’s disease. J Neurochem. 1995;64:1645–54.

    CAS  PubMed  Google Scholar 

  68. Xu Y, Stokes AH, Freeman WM, Kumer SC, Vogt BA, Vrana KE. Tyrosinase mRNA is expressed in human substantia nigra. Brain Res Mol Brain Res. 1997;45:159–62.

    CAS  PubMed  Google Scholar 

  69. Foley JM, Baxter D. On the nature of pigment granules in the cells of the locus coeruleus and substantia nigra. J Neuropathol Exp Neurol. 1958;17:586–98.

    CAS  PubMed  Google Scholar 

  70. Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J, Lucius R. Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson’s disease. Acta. Neuropathol. 2008;116:47–55.

    CAS  Google Scholar 

  71. 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. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res. 2011;19:63–72.

    PubMed Central  PubMed  Google Scholar 

  72. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long–standing Parkinson’s disease. Mov Disord. 1998;13:221–7.

    CAS  PubMed  Google Scholar 

  73. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. 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. 1999;46:598–605.

    CAS  PubMed  Google Scholar 

  74. McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA–DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38:1285–91.

    CAS  PubMed  Google Scholar 

  75. Double KL, Ben–Shachar D, Youdim MB, Zecca L, Riederer P, Gerlach M. Influence of neuromelanin on oxidative pathways within the human substantia nigra. Neurotoxicol Teratol. 2002;24:621–8.

    CAS  PubMed  Google Scholar 

  76. Zareba M, Bober A, Korytowski W, Zecca L, Sarna T. The effect of a synthetic neuromelanin on yield of free hydroxyl radicals generated in model systems. Biochim Biophys Acta. 1995;1271:343–8.

    PubMed  Google Scholar 

  77. Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T. Neuromelanin can protect against iron–mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J Neurochem. 2008;106:1866–75.

    CAS  PubMed  Google Scholar 

  78. Girotto S, Sturlese M, Bellanda M, Tessari I, Cappellini R, Bisaglia M, Bubacco L, Mammi S. Dopamine-derived quinones affect the structure of the redox sensor DJ-1 through modifications at Cys-106 and Cys-53. J Biol Chem. 2012;287:18738–49.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VM. Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome—mediated conformational alterations. J Biol Chem. 2005;280:21212–9.

    CAS  PubMed  Google Scholar 

  80. Baez S, Linderson Y, Segura-Aguilar J. Superoxide dismutase and catalase enhance autoxidation during one-electron reduction of aminochrome by NADPH-cytochrome P-450 reductase. Biochem Mol Med. 1995;54:12–8.

    CAS  PubMed  Google Scholar 

  81. Díaz-Véliz G, Paris I, Mora S, Raisman-Vozari R, Segura-Aguilar J. Copper neurotoxicity in rat substantia nigra and striatum is dependent on DT-diaphorase inhibition. Chem Res Toxicol. 2008;21:1180–5.

    PubMed  Google Scholar 

  82. Segura-Aguilar J, Diaz-Veliz G, Mora S, Herrera-Marschitz M. Inhibition of DT-diaphorase is a requirement for Mn(III) to produce a 6-OH-dopamine like rotational behaviour. Neurotox Res. 2002;4:127–31.

    CAS  PubMed  Google Scholar 

  83. Schultzberg M, Segura-Aguilar J, Lind C. Distribution of DT diaphorase in the rat brain: biochemical and immunohistochemical studies. Neuroscience. 1988;27:763–76.

    CAS  PubMed  Google Scholar 

  84. Díaz-Véliz G, Mora S, Dossi MT, Gómez P, Arriagada C, Montiel J, Aboitiz F, Segura-Aguilar J. Behavioral effects of aminochrome and dopachrome injected in the rat substantia nigra. Pharmacol Biochem Behav. 2002;73:843–50.

    PubMed  Google Scholar 

  85. Díaz-Véliz G, Mora S, Gómez P, Dossi MT, Montiel J, Arriagada C, Aboitiz F, Segura-Aguilar J. Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diapase inhibitor. Pharmacol Biochem Behav. 2004;77:245–51.

    PubMed  Google Scholar 

  86. Díaz-Véliz G, Mora S, Lungenstrass H, Segura-Aguilar J. Inhibition of DT-diaphorase potentiates the in vivo neurotoxic effect of intranigral injection of salsolinol in rats. Neurotox Res. 2004;5:629–33.

    PubMed  Google Scholar 

  87. Nicolis S, Zucchelli M, Monzani E, Casella L. Myoglobin modification by enzyme-generated dopamine reactive species. Chem Eur J. 2008;14:8661–73.

    CAS  PubMed  Google Scholar 

  88. Shen XM, Xia B, Wrona MZ, Dryhurst G. Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson’s disease. Chem Res Toxicol. 1996;9:1117–26.

    CAS  PubMed  Google Scholar 

  89. Zhou ZD, Lim TM. Glutathione conjugates with dopamine-derived quinones to form reactive or non-reactive glutathione-conjugates. Neurochem Res. 2010;35:1805–18.

    CAS  PubMed  Google Scholar 

  90. Zhang F, Dryhurst G. Effects of L-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to idiopathic Parkinson’s disease. J Med Chem. 1994;37:1084–98.

    CAS  PubMed  Google Scholar 

  91. Wolters ECh, Braak H. Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl. 2006;70:309–19.

    PubMed  Google Scholar 

  92. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.

    CAS  PubMed  Google Scholar 

  93. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.

    CAS  PubMed  Google Scholar 

  94. Abbas N, Lücking CB, Ricard S, Dürr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Böhme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson’s Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Hum Mol Genet. 1999;8:567–74.

    CAS  PubMed  Google Scholar 

  95. Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, Brookes AJ, Yamamura Y, Kobayashi T, Wang M, Yoritaka A, Minoshima S, Shimizu N, Mizuno Y. Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the parkin gene. Biochem Biophys Res Commun. 1998;249:754–8.

    CAS  PubMed  Google Scholar 

  96. Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38:1184–91.

    CAS  PubMed  Google Scholar 

  97. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304:1158–60.

    CAS  PubMed  Google Scholar 

  98. Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005;76:672–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256–9.

    CAS  PubMed  Google Scholar 

  100. Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE. A-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2013;73:155–69.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Bohlega SA, Al-Foghom NB. Drug-induced Parkinson’s disease. A clinical review. Neurosciences (Riyadh). 2013;18:215–21.

    Google Scholar 

  102. Allen MT, Levy LS. Parkinson’s disease and pesticide exposure–a new assessment. Crit Rev Toxicol. 2013;43:515–34.

    CAS  PubMed  Google Scholar 

  103. Mullin S, Schapira A. A-Synuclein and mitochondrial dysfunction in Parkinson’s disease. Mol Neurobiol. 2013;47:587–97.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012;31:3038–62.

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Ebrahimi-Fakhari D, Wahlster L, McLean PJ. Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol. 2012;124:153–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Taylor JM, Main BS, Crack PJ. Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int. 2013;62:803–19.

    CAS  PubMed  Google Scholar 

  107. Martinez-Vicente M, Vila M. Alpha-synuclein and protein degradation pathways in Parkinson’s disease: a pathological feed-back loop. Exp Neurol. 2013;247:308–13.

    CAS  PubMed  Google Scholar 

  108. Zafar KS, Siegel D, Ross D. A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. Mol Pharmacol. 2006;70:1079–86.

    CAS  PubMed  Google Scholar 

  109. Zhou ZD, Lim TM. Dopamine (DA) induced irreversible proteasome inhibition via DA derived quinones. Free Radic Res. 2009;43:417–30.

    CAS  PubMed  Google Scholar 

  110. Muñoz P, Huenchuguala S, Paris I, Segura-Aguilar J. Dopamine oxidation and autophagy. Parkinson’s Dis. 2012;920953:1–13.

    Google Scholar 

  111. Kupsch A, Schmidt W, Gizatullina Z, Debska-Vielhaber G, Voges J, Striggow F, Panther P, Schwegler H, Heinze HJ, Vielhaber S, Gellerich FN. 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses. J Neural Transm. 2014. doi:10.1007/s00702-014-1185-3

    Google Scholar 

  112. Khaindrava VG, Kozina EA, Kudrin VS, Kucheryanu VG, Klodt PD, Narkevich VB, Bocharov EV, Nanaev AK, Kryzhanovsky GN, Raevskii KS, Ugrumov MV. Experimental modeling of preclinical and clinical stages of Parkinson’s disease. Bull Exp Biol Med. 2011;150:566–9.

    CAS  PubMed  Google Scholar 

  113. Somayajulu-Niţu M, Sandhu JK, Cohen J, Sikorska M, Sridhar TS, Matei A, Borowy-Borowski H, Pandey S. Paraquat induces oxidative stress, neuronal loss in substantia nigra region and parkinsonism in adult rats: neuroprotection and amelioration of symptoms by water-soluble formulation of coenzyme Q10. BMC Neurosci. 2009. doi:10.1186/1471-2202-10-88.

    Google Scholar 

  114. Mulcahy P, Walsh S, Paucard A, Rea K, Dowd E. Characterisation of a novel model of Parkinson’s disease by intra-striatal infusion of the pesticide rotenone. Neuroscience. 2011;181:234–42.

    CAS  PubMed  Google Scholar 

  115. Moretto A, Colosio C. Biochemical and toxicological evidence of neurological effects of pesticides: the example of Parkinson’s disease. Neurotoxicology. 2011;32:383–91.

    CAS  PubMed  Google Scholar 

  116. Vermeer LM, Florang VR, Doorn JA. Catechol and aldehyde moieties of 3,4-dihydroxyphenylacetaldehyde contribute to tyrosine hydroxylase inhibition and neurotoxicity. Brain Res. 2012;1474:100–9.

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Clinical Pharmacology, ICBM; Faculty of Medicine, University of Chile, Santiago, Chile

    Patricia Muñoz, Catalina Melendez, Irmgard Paris & Juan Segura-Aguilar

  2. Department of Basic Sciences, Faculty of Science, University SantoTomas, Santo Tomas, Chile

    Irmgard Paris

Authors
  1. Patricia Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catalina Melendez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irmgard Paris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan Segura-Aguilar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan Segura-Aguilar .

Editor information

Editors and Affiliations

  1. Bioquímica y Biología Molecular y Gen., Facultad de Enfermería y T.O., Cáceres, Spain

    José M. Fuentes

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Muñoz, P., Melendez, C., Paris, I., Segura-Aguilar, J. (2015). Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis. In: Fuentes, J. (eds) Toxicity and Autophagy in Neurodegenerative Disorders. Current Topics in Neurotoxicity, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-13939-5_11

Download citation

Publish with us

Policies and ethics

Search

Navigation