Skip to main content
SpringerLink
Log in

Overexpressed Alpha-Synuclein Regulated the Nuclear Factor-kappaB Signal Pathway

Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alpha-synuclein is a presynaptic protein which is implicated in some neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, multiple systems atrophy, and Hallervorden-Spatz disease, and its overexpression contributes to the loss of dopaminergic neurons. Although the role of alpha-synuclein in these paradigms has been widely documented, its exact function is still elusive. And the dysfunction of the transcription factor nuclear factor (NF-κB) also exists in many neurodegenerative diseases. In this reason the purpose of this study was to investigate the molecular mechanism of alpha-synuclein’s toxicity and its association with NF-κB by MTT assay, Western blot method, and luciferase assay. Results showed that overexpressed alpha-synuclein and 1-methyl-4-phenylpyridinium (MPP+) suppressed the SH-SY5Y cell viability and attenuate NF-κB-mediated luciferase expression significantly. Moreover, the impairment function was enhanced with the increase of alpha-synuclein protein level. We also found that overexpressed alpha-synuclein localized both in the cytoplasms and nuclei, down-regulated the anti-apoptotic Bcl-2 expression and up-regulated the pro-apoptotic glycogen synthase kinase 3β (GSK3β) protein level. In conclusion, all these findings mentioned above suggested that alpha-synuclein shared some toxic functional homology with neurotoxin MPP+, and the proapoptotic effects of alpha-synuclein might be mediated at least in part by the impairment of NF-κB signaling pathway which involves GSK3β.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  • Aguilera C, Ferna’ndez-Majada V, Inglés-Esteve J, Rodilla V, Espinosa L (2006) Efficient nuclear export of p65-IkBa complexes requires 14-3-3 proteins. J Cell Sci 119:3695–3704

    Google Scholar 

  • Arawaka S, Saito Y, Murayama S, Mori H (1998) Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein. Neurology 51:887–889

    PubMed  CAS  Google Scholar 

  • Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    PubMed  CAS  Google Scholar 

  • Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR (1997) Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275:1930–1933

    Article  PubMed  CAS  Google Scholar 

  • Bernheimer H, Birkmayer W, Hornykiewicz O, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455

    Article  PubMed  CAS  Google Scholar 

  • Bhakar AL, Tannis LL, Zeindler C, Russo MP, Jobin C, Park DS (2002) Constitutive nuclear factor-kappa B activity is required for central neuron survival. J Neurosci 22:8466–8475

    PubMed  CAS  Google Scholar 

  • Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T (1991) Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64:573–584

    Article  PubMed  CAS  Google Scholar 

  • Catz SD, Johnson JL (2001) Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 20:7342–7351

    Article  PubMed  CAS  Google Scholar 

  • Claton DJ, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58:120–129

    Article  Google Scholar 

  • Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD (2001) Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem 77:94–102

    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 

  • Dickson DW, Liu W-K, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Sima A, D’Amato C, Albin R, Gilman S, Yen S-H (1999) Widespread alterations of α-synuclein in multiple system atrophy. Am J Pathol 155:1241–1251

    PubMed  CAS  Google Scholar 

  • Dunnett SB, Bjorklund A (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature 399:A32–A39

    Article  PubMed  CAS  Google Scholar 

  • Fall CP, Bennett Jr JP (1999) Characterization and time course of MPP+-induced apoptosis in human SH-SY5Y neuroblastoma cells. J Neurosci Res 55:620–628

    Article  PubMed  CAS  Google Scholar 

  • Ginger RS, Dalton EC, Ryves WJ, Fukuzawa M, Williams JG, Harwood AJ (2000) Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein. EMBO J 19:5483–5491

    Article  PubMed  CAS  Google Scholar 

  • Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465–8471

    Article  PubMed  CAS  Google Scholar 

  • Gómez-Santos, Ferrer I, Reiriz J, Vinals F, Barrachina M, Ambrosio S (2002) MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells. Brain Res 935:32–39

    Article  PubMed  Google Scholar 

  • Grimes CA, Jope RS (2001a) CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. J Neurochem 78:1219–1232

    Article  PubMed  CAS  Google Scholar 

  • Grimes CA, Jope RS (2001b) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426

    Article  PubMed  CAS  Google Scholar 

  • Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes & Dev 13:1899–1904

    Article  CAS  Google Scholar 

  • Halvorsen EM, Dennis J, Keeney P, Sturgill TW, Tuttle JB, Bennett Jr JB (2002) Methylpyridinium (MPP(+))- and nerve growth factor-induced changes in pro- and anti-apoptotic signaling pathways in SH-SY5Y neuroblastoma cells. Brain Res 952:98–110

    Article  PubMed  CAS  Google Scholar 

  • Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311:467–469

    Article  PubMed  CAS  Google Scholar 

  • Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000) Role of glycogen synthase kinase-3 in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20:2567–2574

    PubMed  CAS  Google Scholar 

  • Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, Silva HA, Kittel A, Saitoh T (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475

    Article  PubMed  CAS  Google Scholar 

  • Iwata A, Miura S, Kanazawa I, Sawada M, Nukina N (2001) alpha-Synuclein forms a complex with transcription factor Elk-1. J Neurochem 77:239–252

    Article  PubMed  CAS  Google Scholar 

  • Kontopoulos E, Parvin JD, Feany MB (2006) α-Synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023

    Article  PubMed  CAS  Google Scholar 

  • Langston JW (1996) The etiology of Parkinson’s disease with emphasis on the MPTP story. Neurology 47:153–160

    Google Scholar 

  • Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Price DL (2002) Human α-synuclein-harboring familial Parkinson’s disease-linked Ala-53 Thr mutation causes neurodegenerative disease with -synuclein aggregation in transgenic mice. PNAS 99:8968–8973

    Article  PubMed  CAS  Google Scholar 

  • Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuronspecific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815

    PubMed  CAS  Google Scholar 

  • Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1267

    Article  PubMed  CAS  Google Scholar 

  • Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6:1072–1078

    Article  PubMed  CAS  Google Scholar 

  • Meller N, Liu YC, Collins TL, Bonnefoy-Berard N, Baier G, Isakov N, Altman A (1996) Direct interaction between protein kinase C theta (PKC theta) and 14-3- 3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function. Mol Cell Biol 16:5782–5791

    PubMed  CAS  Google Scholar 

  • Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) α-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19:5782–5791

    PubMed  CAS  Google Scholar 

  • Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for α-synuclein in the regulation of dopamine biosynthesis. Neurosci 22:3090–3099

    CAS  Google Scholar 

  • Planel E, Sun X, Takashima A (2002) Role of GSK-3β in Alzheimer’s disease pathology. Drug Dev 56:491–510

    Article  CAS  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Iorio GD, Golbe LI, Nussbaum RL (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  PubMed  CAS  Google Scholar 

  • Sanchez JF, Sniderhan LF, Williamson AL, Fan S, Chakraborty-Sett S, Maggirwar SB (2003) Glycogen synthase kinase 3β mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kB signaling. Mol Cell Biol 23:4639–4662

    Article  CAS  Google Scholar 

  • Specht CG, Tigaret CM, Rast GF, Thalhammer A, Rudhard Y, Schoepfer R (2005) Subcellular localisation of recombinant alpha- and gamma-synuclein. Mol Cell Neurosci 28:326–334

    Article  PubMed  CAS  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. PNAS 95:6469–6473

    Article  PubMed  CAS  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  PubMed  CAS  Google Scholar 

  • Thomas GM, Frame S, Goedert M, Nathke I, Polakis P, Cohen P (1999) A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin. FEBS Lett 458:247–251

    Article  PubMed  CAS  Google Scholar 

  • Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi T (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182

    Article  PubMed  CAS  Google Scholar 

  • Wang C-Y, Guttridge DC, Mayo MW, Baldwin AS (1999) NF-kB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol 19:5923–5929

    PubMed  CAS  Google Scholar 

  • Xu J, Kao SY, Lee FJ, Song W, Yankner BA (2002) Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8:600–606

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Zhong N, Wang H, Elias JE, Kim CY, Woldman I, Pifl C, Gygi SP, Geula C, Yankner BA (2005) The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum Mol Genet 14:1231–1241

    Article  PubMed  CAS  Google Scholar 

  • Yu S, Zuo X, Li Y, Zhang C, Zhou M, Zhang YA, Ueda K, Chan P (2004) Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells. Neurosci Lett 367:34–39

    Article  PubMed  CAS  Google Scholar 

  • Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 86:619–628

    Article  Google Scholar 

  • Zhang L, Wang H, Liu D, Liddington R, Fu H (1997) Raf-1 kinase and exoenzyme s interact with 14-3-3 g through a common site involving lysine 49. J Biol Chem 272:13717–13724

    Article  PubMed  CAS  Google Scholar 

  • Zigmond MJ, Stricker EM (1989) Animal models of parkinsonism using selective neurotoxins: clinical and basic implications. Int Rev Neurobiol 31:1–79

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by National Key Basic Research & Development Program (973 project Grant No. 2004CB518906), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT No. IRT0514) and the National Natural Science Foundation of China (No. 30572342 and No. 30271499).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Bioactive Substances and Resources Utilization, Ministry of Education, Beijing, 100050, PR China

    Yuhe Yuan, Jin Jin, Bo Yang, Wei Zhang, Jinfeng Hu, Yun Zhang & Nai-Hong Chen

Authors
  1. Yuhe Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinfeng Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nai-Hong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nai-Hong Chen.

Additional information

Yuhe Yuan and Jin Jin contributed equally to this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, Y., Jin, J., Yang, B. et al. Overexpressed Alpha-Synuclein Regulated the Nuclear Factor-kappaB Signal Pathway. Cell Mol Neurobiol 28, 21–33 (2008). https://doi.org/10.1007/s10571-007-9185-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-007-9185-6

Keywords

search

Navigation