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α-Synuclein increases U251 cells vulnerability to hydrogen peroxide by disrupting calcium homeostasis

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by glial cytoplasmic inclusions containing insoluble α-synuclein. Since Ca2+ plays an important role in cell degeneration, [Ca2+] i in α-synuclein-overexpressed human glioma cells was analyzed by Fura-2 fluorometry. Overexpression of α-synuclein increased the basal level of [Ca2+] i , and a higher Ca2+ response to hydrogen peroxide was further observed. The effect that α-synuclein overexpression caused U251 cells to be more vulnerable to hydrogen peroxide was eliminated by Ca2+ chelator BAPTA-AM or transient receptor potential channels blocker SKF 96365 but not by L-type Ca2+ channel blocker nimodipine. These findings suggest that the dysregulation of cellular Ca2+ homeostasis caused by α-synuclein under oxidative stress may contribute to the glial cell death in MSA.

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References

  • Adamczyk A, Strosznajder JB (2006) Alpha-synuclein potentiates Ca2+ influx through voltage-dependent Ca2+ channels. Neuroreport 17(18):1883–1886

    Article  PubMed  CAS  Google Scholar 

  • Brundin P, Karlsson J et al (2000) Improving the survival of grafted dopaminergic neurons: a review over current approaches. Cell Transplant 9(2):179–195

    PubMed  CAS  Google Scholar 

  • Cahoy JD, Emery B et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278

    Article  PubMed  CAS  Google Scholar 

  • Danzer KM, Haasen D et al (2007) Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 27(34):9220–9232

    Article  PubMed  CAS  Google Scholar 

  • Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95

    PubMed  CAS  Google Scholar 

  • Fan MM, Raymond LA (2007) N-methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 81(5–6):272–293

    Article  PubMed  CAS  Google Scholar 

  • Fortin DL, Nemani VM et al (2005) Neural activity controls the synaptic accumulation of alpha-synuclein. J Neurosci 25(47):10913–10921

    Article  PubMed  CAS  Google Scholar 

  • Furukawa K, Matsuzaki-Kobayashi M et al (2006) Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J Neurochem 97(4):1071–1077

    Article  PubMed  CAS  Google Scholar 

  • Galvin JE, Lee VM et al (2001) Synucleinopathies: clinical and pathological implications. Arch Neurol 58(2):186–190

    Article  PubMed  CAS  Google Scholar 

  • Green KN, LaFerla FM (2008) Linking calcium to Abeta and Alzheimer’s disease. Neuron 59(2):190–194

    Article  PubMed  CAS  Google Scholar 

  • Hettiarachchi NT, Parker A et al (2009) Alpha-Synuclein modulation of Ca2+ signaling in human neuroblastoma (SH-SY5Y) cells. J Neurochem 111(5):1192–1201

    Article  PubMed  CAS  Google Scholar 

  • Jakes R, Spillantini MG et al (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345(1):27–32

    Article  PubMed  CAS  Google Scholar 

  • Larsen KE, Schmitz Y et al (2006) Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci 26(46):11915–11922

    Article  PubMed  CAS  Google Scholar 

  • Lee MK, Stirling W et al (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99(13):8968–8973

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6(3):337–350

    Article  PubMed  CAS  Google Scholar 

  • Mosharov EV, Larsen KE et al (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62(2):218–229

    Article  PubMed  CAS  Google Scholar 

  • Nemani VM, Lu W et al (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65(1):66–79

    Article  PubMed  CAS  Google Scholar 

  • Orrenius S, Zhivotovsky B et al (2003) Regulation of cell death: the calcium–apoptosis link. Nat Rev Mol Cell Biol 4(7):552–565

    Article  PubMed  CAS  Google Scholar 

  • Papp MI, Kahn JE et al (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy–Drager syndrome). J Neurol Sci 94(1–3):79–100

    Article  PubMed  CAS  Google Scholar 

  • Shults CW, Rockenstein E et al (2005) Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 25(46):10689–10699

    Article  PubMed  CAS  Google Scholar 

  • Soper JH, Roy S et al (2008) Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae. Mol Biol Cell 19(3):1093–1103

    Article  PubMed  CAS  Google Scholar 

  • Specht CG, Tigaret CM et al (2005) Subcellular localisation of recombinant alpha- and gamma-synuclein. Mol Cell Neurosci 28(2):326–334

    Article  PubMed  CAS  Google Scholar 

  • Stefanova N, Klimaschewski L et al (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65(5):432–438

    Article  PubMed  CAS  Google Scholar 

  • Stefanova N, Reindl M et al (2005a) Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol 166(3):869–876

    Article  PubMed  CAS  Google Scholar 

  • Stefanova N, Reindl M et al (2005b) In vitro models of multiple system atrophy. Mov Disord 20(Suppl 12):S53–S56

    Article  PubMed  Google Scholar 

  • Surmeier DJ (2007) Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet Neurol 6(10):933–938

    Article  PubMed  CAS  Google Scholar 

  • Tu PH, Galvin JE et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44(3):415–422

    Article  PubMed  CAS  Google Scholar 

  • Volles MJ, Lansbury P T Jr (2003) Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson’s disease. Biochemistry 42(26):7871–7878

    Article  PubMed  CAS  Google Scholar 

  • von Lewinski F, Keller BU (2005) Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS. Trends Neurosci 28(9):494–500

    Article  Google Scholar 

  • Wakabayashi K, Yoshimoto M et al (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249(2–3):180–182

    Article  PubMed  CAS  Google Scholar 

  • Wenning GK, Jellinger KA (2005) The role of alpha-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol 109(2):129–140

    Article  PubMed  CAS  Google Scholar 

  • Wenning GK, Stefanova N et al (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64(3):239–246

    Article  PubMed  CAS  Google Scholar 

  • Yazawa I, Giasson BI et al (2005) Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45(6):847–859

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Schaack J et al (2002) Overexpression of human alpha-synuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res 926(1–2):42–50

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Ministry of Science and Technology of China (2008 BAK03A02 and 2007 CB914100).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People’s Republic of China

    Zhengxin Ying, Fankai Lin, Yang Su, Abida Arshad, Hong Qing & Yulin Deng

  2. Department of Neurology, Movement Disorder and Neurogenetics Research Center, China-Japan Friendship Hospital, Beijing, China

    Weihong Gu

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  1. Zhengxin Ying
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  2. Fankai Lin
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  3. Weihong Gu
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  4. Yang Su
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  5. Abida Arshad
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  6. Hong Qing
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  7. Yulin Deng
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Correspondence to Yulin Deng.

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Ying, Z., Lin, F., Gu, W. et al. α-Synuclein increases U251 cells vulnerability to hydrogen peroxide by disrupting calcium homeostasis. J Neural Transm 118, 1165–1172 (2011). https://doi.org/10.1007/s00702-011-0596-7

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  • DOI: https://doi.org/10.1007/s00702-011-0596-7

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