Neurotoxicity Research

, Volume 36, Issue 4, pp 746–755 | Cite as

Superoxide Dismutases SOD1 and SOD2 Rescue the Toxic Effect of Dopamine-Derived Products in Human SH-SY5Y Neuroblastoma Cells

  • Alice Biosa
  • Federica De Lazzari
  • Anna Masato
  • Roberta Filograna
  • Nicoletta Plotegher
  • Mariano Beltramini
  • Luigi Bubacco
  • Marco BisagliaEmail author
Original Article


The preferential loss of dopaminergic neurons in the substantia nigra pars compacta is one of the pathological hallmarks characterizing Parkinson’s disease. Although the pathogenesis of this disorder is not fully understood, oxidative stress plays a central role in the onset and/or progression of Parkinson’s disease and dopamine itself has been suggested to participate in the preferential neuronal degeneration through the induction of oxidative conditions. In fact, the accumulation of dopamine into the cytosol can lead to the formation of reactive oxygen species as well as highly reactive dopamine-quinones. In the present work, we first analyzed the cellular damage induced by the addition of dopamine (DA) in the culture medium of SH-SY5Y cells, discriminating whether the harmful effects were related to the generation of reactive oxygen species or to the toxicity associated to dopamine-derived quinones. Then, we tested and demonstrated the capability of the antioxidant enzymes SOD1 and SOD2 to protect cells from the noxious effects induced by DA treatment. Our results support further exploration of superoxide dismutating molecules as a therapeutic strategy against Parkinson’s disease.


Dopamine Dopamine quinones Oxidative stress Parkinson’s disease Superoxide dismutation 



  1. Banerjee K, Munshi S, Sen O, Pramanik V, Roy Mukherjee T, Chakrabarti S (2014) Dopamine cytotoxicity involves both oxidative and nonoxidative pathways in SH-SY5Y cells: potential role of alpha-synuclein overexpression and proteasomal inhibition in the etiopathogenesis of Parkinson’s disease. Parkinsons Dis 2014:878935. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517. CrossRefPubMedGoogle Scholar
  3. Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137CrossRefGoogle Scholar
  4. Biosa A, Arduini I, Soriano ME, Giorgio V, Bernardi P, Bisaglia M, Bubacco L (2018a) Dopamine oxidation products as mitochondrial endotoxins, a potential molecular mechanism for preferential neurodegeneration in Parkinson’s disease. ACS Chem Neurosci 9:2849–2858. CrossRefPubMedGoogle Scholar
  5. Biosa A, Sanchez-Martinez A, Filograna R, Terriente-Felix A, Alam SM, Beltramini M, Bubacco L, Bisaglia M, Whitworth AJ (2018b) Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss. Hum Mol Genet 27:1618–1629. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bisaglia M, Greggio E, Maric D, Miller DW, Cookson MR, Bubacco L (2010a)Alpha-synuclein overexpression increases dopamine toxicity in BE2-M17 cells. BMC Neurosci 11:41. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bisaglia M, Soriano ME, Arduini I, Mammi S, Bubacco L (2010b) Molecular characterization of dopamine-derived quinones reactivity toward NADH and glutathione: implications for mitochondrial dysfunction in Parkinson disease. Biochim Biophys Acta 1802:699–706. CrossRefPubMedGoogle Scholar
  8. Bisaglia M, Greggio E, Beltramini M, Bubacco L (2013) Dysfunction of dopamine homeostasis: clues in the hunt for novel Parkinson’s disease therapies. FASEB J 27:2101–2110. CrossRefPubMedGoogle Scholar
  9. Bisaglia M, Filograna R, Beltramini M, Bubacco L (2014) Are dopamine derivatives implicated in the pathogenesis of Parkinson’s disease? Ageing Res Rev 13:107–114. CrossRefPubMedGoogle Scholar
  10. Bonora M, Pinton P (2014) The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Front Oncol 4:302. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255–1261. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cannon JR, Greenamyre JT (2013)Gene-environment interactions in Parkinson’s disease: specific evidence in humans and mammalian models. Neurobiol Dis 57:38–46. CrossRefPubMedGoogle Scholar
  13. De Lazzari F, Bubacco L, Whitworth AJ, Bisaglia M (2018) Superoxide radical dismutation as new therapeutic strategy in Parkinson’s disease. Aging Dis 9:716–728. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Emdadul Haque M, Asanuma M, Higashi Y, Miyazaki I, Tanaka K, Ogawa N (2003)Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. Biochim Biophys Acta 1619:39–52CrossRefGoogle Scholar
  15. Ermak G, Davies KJ (2002) Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol 38:713–721CrossRefGoogle Scholar
  16. Filograna R, Civiero L, Ferrari V, Codolo G, Greggio E, Bubacco L, Beltramini M, Bisaglia M (2015) Analysis of the catecholaminergic phenotype in human SH-SY5Y and BE(2)-M17 neuroblastoma cell lines upon differentiation. PLoS One 10:e0136769. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Filograna R, Beltramini M, Bubacco L, Bisaglia M (2016a)Anti-oxidants in Parkinson’s disease therapy: a critical point of. View Curr Neuropharmacol 14:260–271. CrossRefPubMedGoogle Scholar
  18. Filograna R, Godena VK, Sanchez-Martinez A, Ferrari E, Casella L, Beltramini M, Bubacco L, Whitworth AJ, Bisaglia M (2016b) Superoxide dismutase (SOD)-mimetic M40403 is protective in cell and fly models of paraquat toxicity: implications for Parkinson disease. J Biol Chem 291:9257–9267. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272CrossRefGoogle Scholar
  20. Ganguly U, Ganguly A, Sen O, Ganguly G, Cappai R, Sahoo A, Chakrabarti S (2019) Dopamine cytotoxicity on SH-SY5Y cells: involvement of alpha-synuclein and relevance in the neurodegeneration of sporadic Parkinson’s disease. Neurotox Res 35:898–907. CrossRefPubMedGoogle Scholar
  21. Gimenez-Xavier P et al (2006) The decrease of NAD(P) H has a prominent role in dopamine toxicity. Biochim Biophys Acta 1762:564–574. CrossRefPubMedGoogle Scholar
  22. Graham DG (1978) Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14:633–643PubMedGoogle Scholar
  23. Greggio E, Bergantino E, Carter D, Ahmad R, Costin GE, Hearing VJ, Clarimon J, Singleton A, Eerola J, Hellstrom O, Tienari PJ, Miller DW, Beilina A, Bubacco L, Cookson MR (2005) Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson’s disease. J Neurochem 93:246–256. CrossRefPubMedGoogle Scholar
  24. Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4:600–609. CrossRefPubMedGoogle Scholar
  26. Izumi Y, Sawada H, Yamamoto N, Kume T, Katsuki H, Shimohama S, Akaike A (2005) Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells. J Neurosci Res 82:126–137. CrossRefPubMedGoogle Scholar
  27. Jana S, Sinha M, Chanda D, Roy T, Banerjee K, Munshi S, Patro BS, Chakrabarti S (2011) Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: implications in dopamine cytotoxicity and pathogenesis of Parkinson’s disease. Biochim Biophys Acta 1812:663–673. CrossRefPubMedGoogle Scholar
  28. Klegeris A, Korkina LG, Greenfield SA (1995) Autoxidation of dopamine: a comparison of luminescent and spectrophotometric detection in basic solutions. Free Radic Biol Med 18:215–222CrossRefGoogle Scholar
  29. Lai CT, Yu PH (1997)Dopamine- and L-beta-3,4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. Effects of oxidative stress and antioxidative factors. Biochem Pharmacol 53:363–372CrossRefGoogle Scholar
  30. Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–2293. CrossRefPubMedGoogle Scholar
  31. Puspita L, Chung SY, Shim JW (2017) Oxidative stress and cellular pathologies in Parkinson’s disease. Mol Brain 10:53. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Solomon EI, Sundaram UM, Machonkin TE (1996) Multicopper oxidases and oxygenases. Chem Rev 96:2563–2606. CrossRefPubMedGoogle Scholar
  33. Surmeier DJ (2018) Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J 285:3657–3668. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ (2015) Redox homeostasis and mitochondrial dynamics. Cell Metab 22:207–218. CrossRefPubMedGoogle Scholar
  35. Zelko IN, Mariani TJ, Folz RJ (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD(SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33:337–349CrossRefGoogle Scholar
  36. Zeng XS, Geng WS, Jia JJ, Chen L, Zhang PP (2018) Cellular and molecular basis of neurodegeneration in Parkinson disease. Front Aging Neurosci 10:109. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94:909–950. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Zucca FA, Basso E, Cupaioli FA, Ferrari E, Sulzer D, Casella L, Zecca L (2014) Neuromelanin of the human substantia nigra: an update. Neurotox Res 25:13–23. CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Molecular Physiology and Biophysics Unit, Department of BiologyUniversity of PadovaPadovaItaly
  2. 2.Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden

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