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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.
AuthorsYuhe Yuan, Jin Jin, Bo Yang, Wei Zhang, Jinfeng Hu, Yun Zhang, Nai-Hong Chen
JournalCellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 28 Issue 1 Pg. 21-33 (Jan 2008) ISSN: 1573-6830 [Electronic] United States
PMID17712623 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • alpha-Synuclein
  • Luciferases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • 1-Methyl-4-phenylpyridinium
Topics
  • 1-Methyl-4-phenylpyridinium (toxicity)
  • Cell Line, Tumor
  • Cell Nucleus (drug effects, metabolism)
  • Cell Survival (drug effects)
  • Genes, Reporter
  • Glycogen Synthase Kinase 3 (metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Luciferases (metabolism)
  • NF-kappa B (metabolism)
  • Plasmids (genetics)
  • Protein Transport (drug effects)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Signal Transduction
  • Transfection
  • alpha-Synuclein (metabolism, toxicity)

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