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Papers In Press, published online ahead of print October 22, 2002
IPMC, UMR 6097 CNRS, Valbonne 06560
Corresponding Author: checler{at}ipmc.cnrs.fr
We have examined the influence of
J. Biol. Chem, 10.1074/jbc.M207825200
Submitted on August 1, 2002
Revised on October 22, 2002
Accepted on October 22, 2002
-synuclein lowers p53-dependent apoptotic response in neuronal cells: Abolishment by 6-hydroxydopamine and implication for Parkinson's disease
-synuclein on the responsiveness of TSM1 neuronal cells to apoptotic stimulus. We show that -synuclein drastically lowers basal and staurosporine-stimulated caspase 3 immunoreactivity and activity. This is accompanied by lower DNA fragmentation and reduced number of tunel-positive neurons. Interestingly, -synuclein also diminishes both p53 expression and transcriptional activity. We demonstrate that the antiapoptotic phenotype displayed by -synuclein can be fully reversed by the Parkinson’s disease-associated dopamine derivative 6-hydroxydopamine. Thus, 6-hydroxydopamine fully abolishes the -synuclein-mediated reduction of caspase 3 activity and reverses the associated decrease of p53 expression. 6-hydroxydopamine triggers thioflavin T-positive deposits in -synuclein- but not Mock-transfected TSM1 neurons and drastically increases -synuclein immunoreactivity. Altogether, we suggest that -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 -synuclein aggregation, thereby likely contributing to Parkinson’s disease neuropathology
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