Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson's disease

Abstract

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.