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 Parkinson's disease (PD). Thus, two mutations were reported to be associated with 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 TSM1 neuronal cell lines overexpressing wild-type (wt) alpha-synuclein or the PD-related Ala-53 --> Thr mutant alpha-synuclein. Under basal conditions, acetyl-Asp-Glu-Val-Asp-aldehyde-sensitive caspase activity appears significantly lower in wt alpha-synuclein-expressing cells than in neurons expressing the mutant. Interestingly, wt alpha-synuclein drastically reduces the caspase activation of TSM1 neurons upon three distinct apoptotic stimuli including staurosporine, etoposide, and ceramide C(2) when compared with mock-transfected cells. This inhibitory control of the caspase response triggered by apoptotic agents was abolished by the PD-related pathogenic mutation. Comparison of wild-type and mutated alpha-synuclein-expressing cells also indicates that the former exhibits much less vulnerability in response to staurosporine and etoposide as measured by the sodium 3'-[1-(phenylaminocarbonyl)-3, 4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid assay. Altogether, our study indicates that wild-type alpha-synuclein exerts an antiapoptotic effect in neurons that appears to be abolished by the Parkinson's disease-related mutation, thereby suggesting a possible mechanism underlying both sporadic and familial forms of this neurodegenerative disease.
da Costa
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Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UPR411, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
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D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D019579:Neocortex / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents; D010300:Parkinson Disease / Q000235:genetics*; D019311:Staurosporine / Q000494:pharmacology; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D005047:Etoposide; D020169:Caspases; D019311:Staurosporine