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Published in: Journal of Neural Transmission 3/2011

01-03-2011 | Basic Neurosciences, Genetics and Immunology - Original Article

Alpha-synuclein aggregation is involved in the toxicity induced by ferric iron to SK-N-SH neuroblastoma cells

Authors: Qing He, Ning Song, Huamin Xu, Rong Wang, Junxia Xie, Hong Jiang

Published in: Journal of Neural Transmission | Issue 3/2011

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Abstract

Increased nigral iron levels and intracytoplasmic Lewy bodies (LBs) in the degenerating neurons are found in Parkinson’s disease (PD). Whether LBs formation is involved in the toxicity of iron is largely unknown. In the present study, we observed that the toxicity of ferric iron was enhanced when SK-N-SH cells were overexpressed with wild-type alpha-synuclein. The mitochondrial transmembrane potential (Δψ m) and cell viability were decreased in these cells, while the intracellular reactive oxygen species (ROS) were increased, compared with that of control. More aggregated alpha-synuclein was observed in these cells. However, while silencing the expression of alpha-synuclein in SK-N-SH cells with siRNA, iron-induced toxicity could be partially alleviated, indicated by the returned Δψ m and cell viability and reduced ROS formation compared with that of control. No alpha-synuclein aggregation could be observed in these cells. The results suggest that alpha-synuclein aggregation was involved in the toxicity of iron to SK-N-SH neuroblastoma cells. Targeting the aggregation of alpha-synuclein might provide a therapeutic strategy for PD in the future.
Literature
go back to reference Chiba-Falek O, Lopez GJ, Nussbaum RL (2006) Levels of alpha-synuclein mRNA in sporadic Parkinson disease patients. Mov Disord 21:1703–1708PubMedCrossRef Chiba-Falek O, Lopez GJ, Nussbaum RL (2006) Levels of alpha-synuclein mRNA in sporadic Parkinson disease patients. Mov Disord 21:1703–1708PubMedCrossRef
go back to reference Cole NB, Murphy DD, Lebowitz J, Di Noto L, Levine RL, Nussbaum RL (2005) Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem 280:9678–9690PubMedCrossRef Cole NB, Murphy DD, Lebowitz J, Di Noto L, Levine RL, Nussbaum RL (2005) Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem 280:9678–9690PubMedCrossRef
go back to reference Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822PubMedCrossRef Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822PubMedCrossRef
go back to reference Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52:1830–1836PubMedCrossRef Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52:1830–1836PubMedCrossRef
go back to reference Dexter DT, Sian J, Jenner P, Marsden CD (1993) Implications of alterations in trace element levels in brain in Parkinson’s disease and other neurological disorders affecting the basal ganglia. Adv Neurol 60:273–281PubMed Dexter DT, Sian J, Jenner P, Marsden CD (1993) Implications of alterations in trace element levels in brain in Parkinson’s disease and other neurological disorders affecting the basal ganglia. Adv Neurol 60:273–281PubMed
go back to reference Friedlich AL, Tanzi RE, Rogers JT (2007) The 5′-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry 12:222–223PubMedCrossRef Friedlich AL, Tanzi RE, Rogers JT (2007) The 5′-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry 12:222–223PubMedCrossRef
go back to reference Gal S, Zheng H, Fridkin M, Youdim MB (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95:79–88PubMedCrossRef Gal S, Zheng H, Fridkin M, Youdim MB (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95:79–88PubMedCrossRef
go back to reference Galvin JE, Giasson B, Hurtig HI, Lee VM, Trojanowski JQ (2000) Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol 157:361–368PubMedCrossRef Galvin JE, Giasson B, Hurtig HI, Lee VM, Trojanowski JQ (2000) Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol 157:361–368PubMedCrossRef
go back to reference Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752PubMedCrossRef Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752PubMedCrossRef
go back to reference Goedert M (1999) Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies. Philos Trans R Soc Lond B Biol Sci 354:1101–1118PubMedCrossRef Goedert M (1999) Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies. Philos Trans R Soc Lond B Biol Sci 354:1101–1118PubMedCrossRef
go back to reference Gotz ME, Double K, Gerlach M, Youdim MB, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 1012:193–208PubMedCrossRef Gotz ME, Double K, Gerlach M, Youdim MB, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 1012:193–208PubMedCrossRef
go back to reference Greenamyre JT, Hastings TG (2004) Biomedicine. Parkinson’s––divergent causes, convergent mechanisms. Science 304:1120–1122PubMedCrossRef Greenamyre JT, Hastings TG (2004) Biomedicine. Parkinson’s––divergent causes, convergent mechanisms. Science 304:1120–1122PubMedCrossRef
go back to reference Hardy PA, Gash D, Yokel R, Andersen A, Ai Y, Zhang Z (2005) Correlation of R2 with total iron concentration in the brains of rhesus monkeys. J Magn Reson Imaging 21:118–127PubMedCrossRef Hardy PA, Gash D, Yokel R, Andersen A, Ai Y, Zhang Z (2005) Correlation of R2 with total iron concentration in the brains of rhesus monkeys. J Magn Reson Imaging 21:118–127PubMedCrossRef
go back to reference Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56:446–451PubMedCrossRef Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56:446–451PubMedCrossRef
go back to reference Hornykiewicz O (1998) Biochemical aspects of Parkinson’s disease. Neurology 51:S2–S9PubMed Hornykiewicz O (1998) Biochemical aspects of Parkinson’s disease. Neurology 51:S2–S9PubMed
go back to reference Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 250(Suppl 3):III11–III14PubMed Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 250(Suppl 3):III11–III14PubMed
go back to reference Jiang H, Luan Z, Wang J, Xie J (2006) Neuroprotective effects of iron chelator Desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem Int 49:605–609PubMedCrossRef Jiang H, Luan Z, Wang J, Xie J (2006) Neuroprotective effects of iron chelator Desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem Int 49:605–609PubMedCrossRef
go back to reference Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res 20:345–356PubMedCrossRef Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res 20:345–356PubMedCrossRef
go back to reference Junn E, Mouradian MM (2002) Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett 320:146–150PubMedCrossRef Junn E, Mouradian MM (2002) Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett 320:146–150PubMedCrossRef
go back to reference Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross A, Kretzschmar H, Giese A (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283:10992–11003PubMedCrossRef Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross A, Kretzschmar H, Giese A (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283:10992–11003PubMedCrossRef
go back to reference Lee HJ, Shin SY, Choi C, Lee YH, Lee SJ (2002) Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 277:5411–5417PubMedCrossRef Lee HJ, Shin SY, Choi C, Lee YH, Lee SJ (2002) Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 277:5411–5417PubMedCrossRef
go back to reference Li WJ, Jiang H, Song N, Xie JX (2010) Oxidative stress partially contributes to iron-induced alpha-synuclein aggregation in SK-N-SH cells. Neurotox Res [Epub ahead of print] Li WJ, Jiang H, Song N, Xie JX (2010) Oxidative stress partially contributes to iron-induced alpha-synuclein aggregation in SK-N-SH cells. Neurotox Res [Epub ahead of print]
go back to reference McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRef McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRef
go back to reference Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19:5782–5791PubMed Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19:5782–5791PubMed
go back to reference Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054PubMed Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054PubMed
go back to reference Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ (2008) Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One 3:e1867PubMedCrossRef Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ (2008) Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One 3:e1867PubMedCrossRef
go back to reference Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52:515–520PubMedCrossRef Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52:515–520PubMedCrossRef
go back to reference Seo JH, Rah JC, Choi SH, Shin JK, Min K, Kim HS, Park CH, Kim S, Kim EM, Lee SH, Lee S, Suh SW, Suh YH (2002) Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J 16:1826–1828PubMed Seo JH, Rah JC, Choi SH, Shin JK, Min K, Kim HS, Park CH, Kim S, Kim EM, Lee SH, Lee S, Suh SW, Suh YH (2002) Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J 16:1826–1828PubMed
go back to reference Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841PubMedCrossRef Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841PubMedCrossRef
go back to reference Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK (2009) The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem 110:719–733PubMedCrossRef Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK (2009) The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem 110:719–733PubMedCrossRef
go back to reference Tanner CM (1992) Occupational and environmental causes of parkinsonism. Occup Med 7:503–513PubMed Tanner CM (1992) Occupational and environmental causes of parkinsonism. Occup Med 7:503–513PubMed
go back to reference Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P, Mayeux R, Langston JW (1999) Parkinson disease in twins: an etiologic study. JAMA 281:341–346PubMedCrossRef Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P, Mayeux R, Langston JW (1999) Parkinson disease in twins: an etiologic study. JAMA 281:341–346PubMedCrossRef
go back to reference Tofaris GK, Revesz T, Jacques TS, Papacostas S, Chataway J (2007) Adult-onset neurodegeneration with brain iron accumulation and cortical alpha-synuclein and tau pathology: a distinct clinicopathological entity. Arch Neurol 64:280–282PubMedCrossRef Tofaris GK, Revesz T, Jacques TS, Papacostas S, Chataway J (2007) Adult-onset neurodegeneration with brain iron accumulation and cortical alpha-synuclein and tau pathology: a distinct clinicopathological entity. Arch Neurol 64:280–282PubMedCrossRef
go back to reference Wang J, Jiang H, Xie JX (2007) Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. Eur J Neurosci 25:2766–2772PubMedCrossRef Wang J, Jiang H, Xie JX (2007) Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. Eur J Neurosci 25:2766–2772PubMedCrossRef
go back to reference Xie J, Jiang H, Chen W, Qian Z (2003) Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of Parkinson’s disease. Exp Neurol 182:483–489CrossRef Xie J, Jiang H, Chen W, Qian Z (2003) Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of Parkinson’s disease. Exp Neurol 182:483–489CrossRef
go back to reference Xu HM, Jiang H, Wang J, Luo B, Xie JX (2008) Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells. Neurochem Int 52:1044–1051PubMedCrossRef Xu HM, Jiang H, Wang J, Luo B, Xie JX (2008) Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells. Neurochem Int 52:1044–1051PubMedCrossRef
go back to reference Zhang S, Wang J, Song N, Xie JX, Jiang H (2009) Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol Aging 30:1466–1476PubMedCrossRef Zhang S, Wang J, Song N, Xie JX, Jiang H (2009) Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol Aging 30:1466–1476PubMedCrossRef
Metadata
Title
Alpha-synuclein aggregation is involved in the toxicity induced by ferric iron to SK-N-SH neuroblastoma cells
Authors
Qing He
Ning Song
Huamin Xu
Rong Wang
Junxia Xie
Hong Jiang
Publication date
01-03-2011
Publisher
Springer Vienna
Published in
Journal of Neural Transmission / Issue 3/2011
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI
https://doi.org/10.1007/s00702-010-0453-0

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