Skip to main content
SpringerLink
Log in

Involvement of Endoplasmic Reticulum Stress on the Cell Death Induced by 6-Hydroxydopamine in Human Neuroblastoma SH-SY5Y Cells

  • ORIGINAL PAPER
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Endoplasmic reticulum (ER) dysfunction is known to activate the unfolded protein response, which is characterized by the activation of two divergent processes, i.e., suppression of the initiation process in global protein synthesis and expression of glucose-regulated protein 78 (Bip/Grp78) and the C/EBP homologous transcription factor CHOP/Gadd153. In this study, we examined the expression of CHOP/Gadd153 and Bip/Grp78 in human neuroblastoma SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA), which is used to prepare animal models of Parkinson’s disease. 6-OHDA treatment induced cell death, in a concentration-dependent manner, which was inhibited by co-treatment with an antioxidant N-acetylcysteine. 6-OHDA was also effective in decreasing proteasome activity and in increasing the levels of high molecular ubiquitin-conjugated proteins. Furthermore, 6-OHDA induced a marked increase in the expression of both CHOP/Gadd153 and Bip/Grp78. This increase was prevented by N-acetylcysteine. Taken together, our data indicate that ER dysfunction is at least in part involved in the mechanisms underlying cell death induced by 6-OHDA in SH-SY5Y cells.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Carman LS, Gage FH, Shults CW (1991) Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior. Brain Res 553:275–283

    Article  PubMed  CAS  Google Scholar 

  • Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150

    Article  PubMed  CAS  Google Scholar 

  • Cohen G, Farooqui R, Kesler N (1997) Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow. Proc Natl Acad Sci USA 94:4890–4894

    Article  PubMed  CAS  Google Scholar 

  • Daimier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. II Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122:1401–1402

    Article  PubMed  Google Scholar 

  • Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909

    Article  PubMed  CAS  Google Scholar 

  • Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822

    Article  PubMed  CAS  Google Scholar 

  • Faucheu BA, Martin ME, Beaumont C, Hauw JJ, Agid Y, Hirsch EC (2003) Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson’s disease. J Neurochem 86:1142–1148

    Article  PubMed  CAS  Google Scholar 

  • Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ (1999) Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J 339:135–141

    Article  PubMed  CAS  Google Scholar 

  • Gething MJ, Sambrook J (1990) Transport and assembly processes in the endoplasmic reticulum. Semin Cell Biol 1:65–72

    PubMed  CAS  Google Scholar 

  • Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 6355:33–45

    Article  Google Scholar 

  • Gilbert JJ, Kish SJ, Chang LJ, Morito C, Shannak K, Hornykiewicz O (1988) Dementia, parkinsonism, and motor neuron disease: neurochemical and neuropathological correlates. Ann Neurol 24(5):688–691

    Article  PubMed  CAS  Google Scholar 

  • Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  • Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799

    PubMed  CAS  Google Scholar 

  • Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902

    Article  PubMed  CAS  Google Scholar 

  • Kanesaki T, Saeki M, Ooi Y, Suematsu M, Matsumoto K, Sakuda M, Saito K, Maeda S (1999) Morphine prevents peroxynitrite-induced death of human neuroblastoma SH-SY5Y cells through a direct scavenging action. Eur J Pharmacol 372:319–324

    Article  PubMed  CAS  Google Scholar 

  • Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233

    Article  PubMed  CAS  Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608

    Article  PubMed  CAS  Google Scholar 

  • Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332:462–464

    Article  PubMed  CAS  Google Scholar 

  • Kumar R, Agarwal AK, Seth PK (1995) Free radical-generated neruotoxicity of 6-hydroxydopamine. J Neuochem 65:1906

    CAS  Google Scholar 

  • Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol 75:345–353

    Article  PubMed  CAS  Google Scholar 

  • Li K, Ito H, Tanaka K, Hirano A (1997) Immunocytochemical-co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol 56:125–131

    Article  PubMed  Google Scholar 

  • McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW (2003) Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 179:38–46

    Article  PubMed  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103

    Article  PubMed  CAS  Google Scholar 

  • Ogawa N, Asanuma M, Kondo Y, Hirata H, Nishibayashi S, Mori A, (1994) Changes in lipid peroxidation, Cu/Zn-superoxide dismutase and its mRNA following an intracerebroventricular injection of 6-hydroxydopamine in mice. Brain Res 646:337–340

    Article  PubMed  CAS  Google Scholar 

  • Pelham HR (1989) Control of protein exit from the endoplasmic reticulum. Annu Rev Cell Biol 5:1–23

    Article  PubMed  CAS  Google Scholar 

  • Riederer P, Konradi C, Hebenstreit G, Youdim MB (1989) Neurochemical perspectives to the function of monoamine oxidase. Acta Neurol Scand Suppl 126:41–45

    Google Scholar 

  • Smythies J (2000) Redox aspects of signaling by catecholamines and their metabolites. Antioxid Redox Signal 2:575–583

    Article  PubMed  CAS  Google Scholar 

  • Sofic E, Lange KW, Jellinger K, Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson’s disease. Neurosci Lett 142:128–130

    Article  PubMed  CAS  Google Scholar 

  • Soto OR, Mendez AE, Hermida AA, Munoz PM, Labandeira GL (2000) Autooxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74:1605–1612

    Article  PubMed  Google Scholar 

  • Vroegop SM, Decker DE, Buxser SE (1995) Localization of damage induced by reactive oxygen species in cultured cells. Free Radical Biol Med 18:141–151

    Article  CAS  Google Scholar 

  • Vu PK, Sakamoto KM (2000) Ubiquitin-mediated proteolysis and human disease. Mol Genet Metab 71:261–266

    Article  PubMed  CAS  Google Scholar 

  • Wang XZ, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H, Ron D (1998) Identification of novel stress-induced genes downstream of chop. EMBO J 17:3619–3630

    Article  PubMed  CAS  Google Scholar 

  • Wang XZ, Lawson B, Brewer JW, Zinszner H, Sanjay A, Mi LJ, Boorstein R, Kreibich G, Hendershot LM, Ron D (1996) Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol Cell Biol 16:4273–4280

    PubMed  CAS  Google Scholar 

  • Welihinda AA, Tirasophon W, Kaufman RJ (1999) The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expression 7:293–300

    PubMed  CAS  Google Scholar 

  • Yoshida H, Haze K, Yanagi H, Yura T, Mori K (1999) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 274:2592

    PubMed  CAS  Google Scholar 

  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000) Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97:13354–13359

    Article  PubMed  CAS  Google Scholar 

  • Zigmond MJ, Stricker EM (1984) Parkinson’s disease: studies with an animal model. Life Sci 35:5–18

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Departments of Pharmacotherapeutics, Setsunan University, 45-1 Nagaotoge-cho, 573-0101, Hirakata, Osaka, Japan

    Akiko Yamamuro, Yasuhiro Yoshioka & Sadaaki Maeda

  2. Faculty of Pharmaceutical Sciences, Departments of Pharmacology, Setsunan University, 45-1 Nagaotoge-cho, 573-0101, Hirakata, Osaka, Japan

    Kiyokazu Ogita

Authors
  1. Akiko Yamamuro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuhiro Yoshioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kiyokazu Ogita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sadaaki Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akiko Yamamuro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamamuro, A., Yoshioka, Y., Ogita, K. et al. Involvement of Endoplasmic Reticulum Stress on the Cell Death Induced by 6-Hydroxydopamine in Human Neuroblastoma SH-SY5Y Cells. Neurochem Res 31, 657–664 (2006). https://doi.org/10.1007/s11064-006-9062-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9062-6

Keywords

Search

Navigation