Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson's disease.
We have examined the influence of alpha-synuclein on the responsiveness of TSM1 neuronal cells to apoptotic stimulus. We show that alpha-synuclein drastically lowers basal and staurosporine-stimulated caspase 3 immunoreactivity and activity. This is accompanied by lower DNA fragmentation and reduced number of terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL)-positive neurons. Interestingly, alpha-synuclein also diminishes both p53 expression and transcriptional activity. We demonstrate that the antiapoptotic phenotype displayed by alpha-synuclein can be fully reversed by the Parkinson's disease-associated dopamine derivative 6-hydroxydopamine. Thus, 6-hydroxydopamine fully abolishes the alpha-synuclein-mediated reduction of caspase 3 activity and reverses the associated decrease of p53 expression. 6-Hydroxydopamine triggers thioflavin T-positive deposits in alpha-synuclein, but not mock-transfected TSM1 neurons, and drastically increases alpha-synuclein immunoreactivity. Altogether, we suggest that alpha-synuclein lowers the p53-dependent caspase 3 activation of TSM1 in response to apoptotic stimuli and we propose that the natural toxin 6-hydroxydopamine abolishes this antiapoptotic phenotype by triggering alpha-synuclein aggregation, thereby likely contributing to Parkinson's disease neuropathology.
Alves Da Costa
Cristine
C
Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France.
Paitel
Erwan
E
Vincent
Bruno
B
Checler
Frédéric
F
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007668:Kidney; D007700:Kinetics; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology* / Q000503:physiopathology; D011994:Recombinant Proteins / Q000378:metabolism; D051843:Synucleins; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D016159:Tumor Suppressor Protein p53; D051844:alpha-Synuclein; D016627:Oxidopamine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases