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Role of Aldehyde Dehydrogenase 2 in 1-Methy-4-Phenylpyridinium Ion-Induced Aldehyde Stress and Cytotoxicity in PC12 Cells

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Abstract

Aldehyde stress contributes to molecular mechanisms of cell death and the pathogenesis of Parkinson’s disease (PD). The neurotoxin 1-Methy-4-Phenylpyridinium Ion (MPP+) is commonly used to model PD. Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme detoxifying aldehydes. The aim of this study is to evaluate whether MPP+-induced neurotoxicity is involved in aldehyde stress by modulation of ALDH2. Our results demonstrated that treatment of PC12 cells with MPP+ leads to aldehyde stress by increasing in loads of malondialdehyde and 4-hydroxynonenal, which indicated that MPP+-induced aldehyde stress contributes to its cytotoxicity in PC12 cells. We also showed that MPP+ up-regulates the expression and activity of ALDH2 in PC12 cells and that inhibition of ALDH2 by its specific inhibitor daidzin prevents MPP+-induced decrease in cell viability and increases in apoptosis, oxidative stress and aldehyde stress in PC12 cells. These findings suggest that aldehyde stress contributes to MPP+-induced toxicity in PC12 cells by upregulation of ALDH2. This study provides a novel insight into the role of ALDH2 in the neurotoxicity of MPP+.

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References

  1. Dawson TM, Dawson VL (2002) Neuroprotective and neurorestorative strategies for Parkinson’s disease. Nat Neurosci 5(Suppl):1058–1061

    Article  CAS  PubMed  Google Scholar 

  2. Wood PL, Khan MA, Kulow SR, Mahmood SA, Moskal JR (2006) Neurotoxicity of reactive aldehydes: the concept of “aldehyde load” as demonstrated by neuroprotection with hydroxylamines. Brain Res 1095:190–199

    Article  CAS  PubMed  Google Scholar 

  3. Wood PL, Khan MA, Moskal JR (2007) The concept of “aldehyde load” in neurodegenerative mechanisms: cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line. Brain Res 1145:150–156

    Article  CAS  PubMed  Google Scholar 

  4. Wood PL (2006) Neurodegeneration and aldehyde load: from concept to therapeutics. J Psychiatry Neurosci 31:296–297

    PubMed Central  PubMed  Google Scholar 

  5. Ellis EM (2007) Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol Ther 115:13–24

    Article  CAS  PubMed  Google Scholar 

  6. Uchida K (2000) Role of reactive aldehyde in cardiovascular diseases. Free Radic Biol Med 28:1685–1696

    Article  CAS  PubMed  Google Scholar 

  7. Aldini G, Dalle-Donne I, Facino RM, Milzani A, Carini M (2007) Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls. Med Res Rev 27:817–868

    Article  CAS  PubMed  Google Scholar 

  8. Jinsmaa Y, Florang VR, Rees JN, Mexas LM, Eckert LL et al (2011) Dopamine-derived biological reactive intermediates and protein modifications: implications for Parkinson’s disease. Chem Biol Interact 192:118–121

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Qin Z, Hu D, Han S, Reaney SH, Di Monte DA et al (2007) Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation. J Biol Chem 282:5862–5870

    Article  CAS  PubMed  Google Scholar 

  10. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER et al (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci USA 93:2696–2701

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Selley ML (1998) (E)-4-hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson’s disease. Free Radic Biol Med 25:169–174

    Article  CAS  PubMed  Google Scholar 

  12. Farooqui T, Farooqui AA (2011) Lipid-mediated oxidative stress and inflammation in the pathogenesis of Parkinson’s disease. Parkinsons Dis 2011:247467

    PubMed Central  PubMed  Google Scholar 

  13. Xiang W, Schlachetzki JC, Helling S, Bussmann JC, Berlinghof M et al (2013) Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Mol Cell Neurosci 54:71–83

    Article  CAS  PubMed  Google Scholar 

  14. Przedborski S, Tieu K, Perier C, Vila M (2004) MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36:375–379

    Article  CAS  PubMed  Google Scholar 

  15. Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219

    Article  CAS  PubMed  Google Scholar 

  16. Zhu Q, Wang J, Zhang Y, Sun S (2012) Mechanisms of MPP(+)-induced PC12 cell apoptosis via reactive oxygen species. J Huazhong Univ Sci Technolog Med Sci 32:861–866

    Article  CAS  PubMed  Google Scholar 

  17. Zawada WM, Banninger GP, Thornton J, Marriott B, Cantu D et al (2011) Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade. J Neuroinflammation 8:129

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Tang XQ, Fan LL, Li YJ, Shen XT, Zhuan YY et al (2011) Inhibition of hydrogen sulfide generation contributes to 1-methy-4-phenylpyridinium ion-induced neurotoxicity. Neurotox Res 19:403–411

    Article  CAS  PubMed  Google Scholar 

  19. Qian JJ, Cheng YB, Yang YP, Mao CJ, Qin ZH et al (2008) Differential effects of overexpression of wild-type and mutant human alpha-synuclein on MPP+ -induced neurotoxicity in PC12 cells. Neurosci Lett 435:142–146

    Article  CAS  PubMed  Google Scholar 

  20. Wu Y, Shang Y, Sun S, Liang H, Liu R (2007) Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. Apoptosis 12:1365–1375

    Article  CAS  PubMed  Google Scholar 

  21. Yamamoto N, Sawada H, Izumi Y, Kume T, Katsuki H et al (2007) Proteasome inhibition induces glutathione synthesis and protects cells from oxidative stress: relevance to Parkinson disease. J Biol Chem 282:4364–4372

    Article  CAS  PubMed  Google Scholar 

  22. Tang XQ, Li YJ, Zhao J, Shen XT, Yang CT et al (2010) Neuroprotective effect of asymmetric dimethylarginine against 1-methyl-4-phenylpyridinium ion-induced damage in PC12 cells. Clin Exp Pharmacol Physiol 37:530–535

    Article  CAS  PubMed  Google Scholar 

  23. Siddiqui MA, Kumar V, Kashyap MP, Agarwal M, Singh AK et al (2012) Short-term exposure of 4-hydroxynonenal induces mitochondria-mediated apoptosis in PC12 cells. Hum Exp Toxicol 31:336–345

    Article  CAS  PubMed  Google Scholar 

  24. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD et al (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321:1493–1495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Hyun DH, Lee MH, Halliwell B, Jenner P (2002) Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation: a mechanism contributing to neurodegeneration? J Neurochem 83:360–370

    Article  CAS  PubMed  Google Scholar 

  26. Lee WC, Wong HY, Chai YY, Shi CW, Amino N et al (2012) Lipid peroxidation dysregulation in ischemic stroke: plasma 4-HNE as a potential biomarker? Biochem Biophys Res Commun 425:842–847

    Article  CAS  PubMed  Google Scholar 

  27. Ohsawa I, Nishimaki K, Yasuda C, Kamino K, Ohta S (2003) Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells. J Neurochem 84:1110–1117

    Article  CAS  PubMed  Google Scholar 

  28. Keung WM (2001) Biogenic aldehyde(s) derived from the action of monoamine oxidase may mediate the antidipsotropic effect of daidzin. Chem Biol Interact 130–132:919–930

    Article  PubMed  Google Scholar 

  29. Keung WM, Vallee BL (1993) Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase. Proc Natl Acad Sci USA 90:1247–1251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Sai T, Uchida K, Nakayama H (2013) Involvement of monoamine oxidase-B in the acute neurotoxicity of MPTP in embryonic and newborn mice. Exp Toxicol Pathol 65:365–373

    Article  CAS  PubMed  Google Scholar 

  31. Hsieh YC, Mounsey RB, Teismann P (2011) MPP(+)-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress. Naunyn Schmiedebergs Arch Pharmacol 384:157–167

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Jin BK, Shin DY, Jeong MY, Gwag MR, Baik HW et al (1998) Melatonin protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity in rats. Neurosci Lett 245:61–64

    Article  CAS  PubMed  Google Scholar 

  33. Jang YJ, Kim J, Shim J, Byun S, Oak MH et al (2011) Kaempferol attenuates 4-hydroxynonenal-induced apoptosis in PC12 cells by directly inhibiting NADPH oxidase. J Pharmacol Exp Ther 337:747–754

    Article  CAS  PubMed  Google Scholar 

  34. Mattammal MB, Haring JH, Chung HD, Raghu G, Strong R (1995) An endogenous dopaminergic neurotoxin: implication for Parkinson’s disease. Neurodegeneration 4:271–281

    Article  CAS  PubMed  Google Scholar 

  35. Burke WJ, Li SW, Williams EA, Nonneman R, Zahm DS (2003) 3,4-Dihydroxyphenylacetaldehyde is the toxic dopamine metabolite in vivo: implications for Parkinson’s disease pathogenesis. Brain Res 989:205–213

    Article  CAS  PubMed  Google Scholar 

  36. Rojas P, Serrano-Garcia N, Medina-Campos ON, Pedraza-Chaverri J, Maldonado PD et al (2011) S-Allylcysteine, a garlic compound, protects against oxidative stress in 1-methyl-4-phenylpyridinium-induced parkinsonism in mice. J Nutr Biochem 22:937–944

    Article  CAS  PubMed  Google Scholar 

  37. Chiueh CC, Andoh T, Lai AR, Lai E, Krishna G (2000) Neuroprotective strategies in Parkinson’s disease: protection against progressive nigral damage induced by free radicals. Neurotox Res 2:293–310

    Article  CAS  PubMed  Google Scholar 

  38. Chan KC, Mong MC, Yin MC (2009) Antioxidative and anti-inflammatory neuroprotective effects of astaxanthin and canthaxanthin in nerve growth factor differentiated PC12 cells. J Food Sci 74:H225–H231

    Article  CAS  PubMed  Google Scholar 

  39. Cheng B, Yang X, Chen C, Cheng D, Xu X et al (2010) D-beta-hydroxybutyrate prevents MPP+ -induced neurotoxicity in PC12 cells. Neurochem Res 35:444–451

    Article  CAS  PubMed  Google Scholar 

  40. Conklin D, Prough R, Bhatanagar A (2007) Aldehyde metabolism in the cardiovascular system. Mol BioSyst 3:136–150

    Article  CAS  PubMed  Google Scholar 

  41. Vasiliou V, Pappa A, Estey T (2004) Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism. Drug Metab Rev 36:279–299

    Article  CAS  PubMed  Google Scholar 

  42. Vasiliou V, Nebert DW (2005) Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics 2:138–143

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Yoval-Sanchez B, Rodriguez-Zavala JS (2012) Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts. Chem Res Toxicol 25:722–729

    Article  CAS  PubMed  Google Scholar 

  44. Solito R, Corti F, Chen CH, Mochly-Rosen D, Giachetti A et al (2013) Mitochondrial aldehyde dehydrogenase-2 activation prevents beta-amyloid-induced endothelial cell dysfunction and restores angiogenesis. J Cell Sci 126:1952–1961

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Ohta S, Ohsawa I, Kamino K, Ando F, Shimokata H (2004) Mitochondrial ALDH2 deficiency as an oxidative stress. Ann N Y Acad Sci 1011:36–44

    Article  CAS  PubMed  Google Scholar 

  46. Ma H, Guo R, Yu L, Zhang Y, Ren J (2011) Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde. Eur Heart J 32:1025–1038

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. He L, Liu B, Dai Z, Zhang HF, Zhang YS et al (2012) Alpha lipoic acid protects heart against myocardial ischemia-reperfusion injury through a mechanism involving aldehyde dehydrogenase 2 activation. Eur J Pharmacol 678:32–38

    Article  CAS  PubMed  Google Scholar 

  48. Kong D, Kotraiah V (2012) Modulation of aldehyde dehydrogenase activity affects (±)-4-hydroxy-2E-nonenal (HNE) toxicity and HNE-protein adduct levels in PC12 cells. J Mol Neurosci 47:595–603

    Article  CAS  PubMed  Google Scholar 

  49. Wey MC, Fernandez E, Martinez PA, Sullivan P, Goldstein DS et al (2012) Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson’s disease. PLoS ONE 7:e31522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Fitzmaurice AG, Rhodes SL, Lulla A, Murphy NP, Lam HA et al (2013) Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci USA 110:636–641

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Klaidman LK, Adams JD Jr, Leung AC, Kim SS, Cadenas E (1993) Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase. Free Radic Biol Med 15:169–179

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by Natural Science Foundation of China (81200986, 81202518), Natural Science Foundation of Hunan Province, China (11JJ3117) and the construct program of the key discipline in Hunan province.

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Authors and Affiliations

  1. Department of Neurology, Nanhua Affiliated Hospital, University of South China, 336 E Dongfeng Road, Hengyang, 421001, Hunan, People’s Republic of China

    Ai-Hua Chen, Ping Zhang, Wei Zou & Xiao-Qing Tang

  2. Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People’s Republic of China

    Ai-Hua Chen, Wei-Lan Yin & Xiao-Qing Tang

  3. Department of Anatomy, Medical College, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Li Wang

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  1. Ai-Hua Chen
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  2. Ping Zhang
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  3. Wei-Lan Yin
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  4. Li Wang
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  5. Wei Zou
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Correspondence to Wei Zou or Xiao-Qing Tang.

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Ai-Hua Chen and Ping Zhang have contributed equally to this work.

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Chen, AH., Zhang, P., Yin, WL. et al. Role of Aldehyde Dehydrogenase 2 in 1-Methy-4-Phenylpyridinium Ion-Induced Aldehyde Stress and Cytotoxicity in PC12 Cells. Neurochem Res 39, 1767–1775 (2014). https://doi.org/10.1007/s11064-014-1376-1

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  • DOI: https://doi.org/10.1007/s11064-014-1376-1

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