title: 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.
abstract: 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.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire of Centre National de la Recherche Scientifique, UMR6097, 06560 Valbonne, France.
authors.forename: Cristine Alves
authors.initials: CA
authors.lastname: da Costa
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
mesh_terms: 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
chemical_list: 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