Wild-type but not Parkinson's disease-related Ala-53 -> Thr mutant alpha-synuclein protects neuronal cells from apoptotic stimuli

Recent works suggest that alpha-synuclein could play a central role in Park inson's disease (PD), Thus, two mutations were reported to be associated wi th rare autosomal dominant forms of the disease. We examined whether alpha- synuclein could modulate the caspase-mediated response and vulnerability of murine neurons in response to various apoptotic stimuli. We established TS M1 neuronal cell lines overexpressing wild-type (wt) alpha-synuclein or the PD-related Ala-SS --> Thr mutant alpha-synuclein, Under basal conditions, acetyl-Asp-Glu-Val-Asp-aldehyde-sensitive caspase activity appears signific antly lower in wt alpha-synuclein-expressing cells than in neurons expressi ng the mutant. Interestingly, wt alpha-synuclein drastically reduces the ca spase activation of TSM1 neurons upon three distinct apoptotic stimuli incl uding staurosporine, etoposide, and ceramide C-2 when compared with mock-tr ansfected cells. This inhibitory control of the caspase response triggered by apoptotic agents was abolished by the PD-related pathogenic mutation. Co mparison of wildtype and mutated alpha-synuclein-expressing cells also indi cates that the former exhibits much less vulnerability in response to staur osporine and etoposide as measured by the sodium 3'-[1-(phenylaminocarbonyl )-3,4-tetrazolium]- bis(4-methoxy-B-nitro)benzenesulfonic acid assay. Altog ether, our study indicates that wild-type alpha-synuclein exerts an antiapo ptotic effect in neurons that appears to be abolished by the Parkinson's di sease related mutation, thereby suggesting a possible mechanism underlying both sporadic and familial forms of this neurodegenerative disease.