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.
da Costa
Cristine Alves
CA
Institut de Pharmacologie Moléculaire et Cellulaire of Centre National de la Recherche Scientifique, UMR6097, 06560 Valbonne, France.
Masliah
Eliezer
E
Checler
Frédéric
F
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000209:etiology*; D010641:Phenotype; D051843:Synucleins; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D051844:alpha-Synuclein; D051846:beta-Synuclein
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D016159:Tumor Suppressor Protein p53; D051844:alpha-Synuclein; D051846:beta-Synuclein; D016627:Oxidopamine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases