Beta-synuclein displays an antiapoptotic p53-dependent phenotype and protects neurons from 6-hydroxydopamine-induced caspase 3 activation: cross-talk with alpha-synuclein and implication for Parkinson's disease.
We have established stable transfectants expressing beta-synuclein in TSM1 neurons. We show that in basal and staurosporine-induced conditions the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL)-positive beta-synuclein-expressing neurons was drastically lower than in mock-transfected TSM1 cells. This was accompanied by a lower DNA fragmentation as evidenced by the reduction of propidium iodide incorporation measured by fluorescence-activated cell sorter analysis. beta-Synuclein strongly reduces staurosporine-induced caspase 3 activity and immunoreactivity. We establish that beta-synuclein triggers a drastic reduction of p53 expression and transcriptional activity. This was accompanied by increased Mdm2 immunoreactivity while p38 expression appeared enhanced, indicating that beta-synuclein- induced p53 down-regulation likely occurs at a post-transcriptional level. We showed previously that alpha-synuclein displays an antiapoptotic function that was abolished by the dopaminergic derived toxin 6-hydroxydopamine (6OHDA). Interestingly, beta-synuclein retains its ability to protect TSM1 neurons even after 6OHDA treatment. Furthermore, beta-synuclein restores the antiapoptotic function of alpha-synuclein in 6OHDA-treated neurons. Altogether, our data document for the first time that beta-synuclein protects neurons from staurosporine and 6OHDA- stimulated caspase activation in a p53-dependent manner. Our observation that beta-synuclein contributes to restoration of the alpha-synuclein antiapoptotic function abolished by 6OHDA may have direct implications for Parkinson's disease pathology. In this context, the cross-talk between these two parent proteins is discussed.[1]References
- Beta-synuclein displays an antiapoptotic p53-dependent phenotype and protects neurons from 6-hydroxydopamine-induced caspase 3 activation: cross-talk with alpha-synuclein and implication for Parkinson's disease. da Costa, C.A., Masliah, E., Checler, F. J. Biol. Chem. (2003) [Pubmed]
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