title: Overexpressed alpha-synuclein regulated the nuclear factor-kappaB signal pathway.
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-kappaB) 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-kappaB 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-kappaB-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 3beta (GSK3beta) 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-kappaB signaling pathway which involves GSK3beta.
authors: 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.
authors: Yuhe
authors: Y
authors: Yuan
authors: Jin
authors: J
authors: Jin
authors: Bo
authors: B
authors: Yang
authors: Wei
authors: W
authors: Zhang
authors: Jinfeng
authors: J
authors: Hu
authors: Yun
authors: Y
authors: Zhang
authors: Nai-Hong
authors: NH
authors: Chen
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity
chemical_list: D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051844:alpha-Synuclein; D008156:Luciferases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D015655:1-Methyl-4-phenylpyridinium
references: Science. 2000 Feb 18;287(5456):1265-9
references: 10678833
references: EMBO J. 2000 Oct 16;19(20):5483-91
references: 11032815
references: J Neurosci Res. 1999 Mar 1;55(5):620-8
references: 10082084
references: J Neurosci. 2002 Oct 1;22(19):8466-75
references: 12351721
references: J Neurochem. 2001 Apr;77(1):239-52
references: 11279280
references: FEBS Lett. 1999 Sep 17;458(2):247-51
references: 10481074
references: Neurology. 1998 Sep;51(3):887-9
references: 9748051
references: Nature. 1984 Oct 4-10;311(5985):467-9
references: 6332989
references: J Neurosci. 2000 Apr 1;20(7):2567-74
references: 10729337
references: J Neurol Sci. 1973 Dec;20(4):415-55
references: 4272516
references: Science. 1997 Jun 27;276(5321):2045-7
references: 9197268
references: Neurosci Lett. 2004 Aug 26;367(1):34-9
references: 15308292
references: Cell. 1996 Nov 15;87(4):619-28
references: 8929531
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73
references: 12084935
references: Mol Cell Biol. 2003 Jul;23(13):4649-62
references: 12808104
references: Mol Cell Neurosci. 2005 Feb;28(2):326-34
references: 15691713
references: Science. 2003 Oct 31;302(5646):819-22
references: 14593166
references: Int Rev Neurobiol. 1989;31:1-79
references: 2689379
references: Brain Res. 2002 May 10;935(1-2):32-9
references: 12062470
references: Oncogene. 2001 Nov 1;20(50):7342-51
references: 11704864
references: Mol Cell Biol. 1999 Sep;19(9):5923-9
references: 10454539
references: Nature. 1999 Jun 24;399(6738 Suppl):A32-9
references: 10392578
references: Neurology. 1996 Dec;47(6 Suppl 3):S153-60
references: 8959984
references: Hum Mol Genet. 2006 Oct 15;15(20):3012-23
references: 16959795
references: Nat Med. 2002 Jun;8(6):600-6
references: 12042811
references: Cell. 1991 Feb 8;64(3):573-84
references: 1846781
references: Brain Res. 2002 Oct 11;952(1):98-110
references: 12363409
references: J Biol Chem. 1997 May 23;272(21):13717-24
references: 9153224
references: J Neurosci. 2002 Apr 15;22(8):3090-9
references: 11943812
references: Science. 1997 Mar 28;275(5308):1930-4
references: 9072970
references: Mol Cell Biol. 1996 Oct;16(10):5782-91
references: 8816492
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73
references: 9600990
references: Am J Pathol. 1999 Oct;155(4):1241-51
references: 10514406
references: Nature. 1997 Aug 28;388(6645):839-40
references: 9278044
references: Neurosci Lett. 1998 Jun 19;249(2-3):180-2
references: 9682846
references: J Neurochem. 2001 Sep;78(6):1219-32
references: 11579131
references: Neuron. 1995 Feb;14(2):467-75
references: 7857654
references: Hum Mol Genet. 2005 May 1;14(9):1231-41
references: 15790595
references: Biochemistry. 2003 Jul 22;42(28):8465-71
references: 12859192
references: J Neurosci. 1999 Jul 15;19(14):5782-91
references: 10407019
references: J Neurochem. 2001 Apr;77(1):94-102
references: 11279265
references: J Cell Sci. 2006 Sep 1;119(Pt 17):3695-704
references: 16931600
references: Prog Neurobiol. 2001 Nov;65(4):391-426
references: 11527574
references: Am J Pathol. 1998 Apr;152(4):879-84
references: 9546347
references: J Neurosci. 1988 Aug;8(8):2804-15
references: 3411354
references: Genes Dev. 1999 Aug 1;13(15):1899-911
references: 10444588
references: J Neurosci Res. 1999 Oct 1;58(1):120-9
references: 10491577
references: Nat Neurosci. 2003 Oct;6(10):1072-8
references: 12947408