14-3-3theta protects against neurotoxicity in a cellular Parkinson's disease model through inhibition of the apoptotic factor Bax

PLoS One. 2011;6(7):e21720. doi: 10.1371/journal.pone.0021720. Epub 2011 Jul 20.


Disruption of 14-3-3 function by alpha-synuclein has been implicated in Parkinson's disease. As 14-3-3s are important regulators of cell death pathways, disruption of 14-3-3s could result in the release of pro-apoptotic factors, such as Bax. We have previously shown that overexpression of 14-3-3θ reduces cell loss in response to rotenone and MPP(+) in dopaminergic cell culture and reduces cell loss in transgenic C. elegans that overexpress alpha-synuclein. In this study, we investigate the mechanism for 14-3-3θ's neuroprotection against rotenone toxicity. While 14-3-3s can inhibit many pro-apoptotic factors, we demonstrate that inhibition of one factor in particular, Bax, is important to 14-3-3s' protection against rotenone toxicity in dopaminergic cells. We found that 14-3-3θ overexpression reduced Bax activation and downstream signaling events, including cytochrome C release and caspase 3 activation. Pharmacological inhibition or shRNA knockdown of Bax provided protection against rotenone, comparable to 14-3-3θ's neuroprotective effects. A 14-3-3θ mutant incapable of binding Bax failed to protect against rotenone. These data suggest that 14-3-3θ's neuroprotective effects against rotenone are at least partially mediated by Bax inhibition and point to a potential therapeutic role of 14-3-3s in Parkinson's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Animals
  • Apoptosis / drug effects*
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Immunoprecipitation
  • Membrane Potential, Mitochondrial / drug effects
  • Neurotoxins / toxicity*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Rotenone / toxicity*
  • Signal Transduction / drug effects
  • bcl-2-Associated X Protein / antagonists & inhibitors*
  • bcl-2-Associated X Protein / metabolism


  • 14-3-3 Proteins
  • Neurotoxins
  • bcl-2-Associated X Protein
  • Rotenone