Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli.
Identifieur interne : 003E71 ( Main/Merge ); précédent : 003E70; suivant : 003E72Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli.
Auteurs : C A Da Costa [France] ; K. Ancolio ; F. CheclerSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2000.
English descriptors
- KwdEn :
- Adult, Apoptosis (genetics), Caspases (drug effects), Ceramides (pharmacology), Cysteine Proteinase Inhibitors (pharmacology), Etoposide (pharmacology), Humans, Mutation, Neocortex (cytology), Neocortex (physiology), Nerve Tissue Proteins (genetics), Neurons (physiology), Neuroprotective Agents, Parkinson Disease (genetics), Staurosporine (pharmacology), Synucleins, Transfection, alpha-Synuclein.
- MESH :
- chemical , drug effects : Caspases.
- cytology : Neocortex.
- genetics : Apoptosis, Nerve Tissue Proteins, Parkinson Disease.
- chemical , pharmacology : Ceramides, Cysteine Proteinase Inhibitors, Etoposide, Staurosporine.
- physiology : Neocortex, Neurons.
- Adult, Humans, Mutation, Neuroprotective Agents, Synucleins, Transfection, alpha-Synuclein.
Abstract
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.
DOI: 10.1074/jbc.M002413200
PubMed: 10818098
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli.</title><author><name sortKey="Da Costa, C A" sort="Da Costa, C A" uniqKey="Da Costa C" first="C A" last="Da Costa">C A Da Costa</name><affiliation wicri:level="3"><nlm:affiliation>Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UPR411, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UPR411, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Valbonne</settlement></placeName></affiliation></author><author><name sortKey="Ancolio, K" sort="Ancolio, K" uniqKey="Ancolio K" first="K" last="Ancolio">K. Ancolio</name></author><author><name sortKey="Checler, F" sort="Checler, F" uniqKey="Checler F" first="F" last="Checler">F. 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Ancolio</name></author><author><name sortKey="Checler, F" sort="Checler, F" uniqKey="Checler F" first="F" last="Checler">F. Checler</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="ISSN">0021-9258</idno><imprint><date when="2000" type="published">2000</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Apoptosis (genetics)</term><term>Caspases (drug effects)</term><term>Ceramides (pharmacology)</term><term>Cysteine Proteinase Inhibitors (pharmacology)</term><term>Etoposide (pharmacology)</term><term>Humans</term><term>Mutation</term><term>Neocortex (cytology)</term><term>Neocortex (physiology)</term><term>Nerve Tissue Proteins (genetics)</term><term>Neurons (physiology)</term><term>Neuroprotective Agents</term><term>Parkinson Disease (genetics)</term><term>Staurosporine (pharmacology)</term><term>Synucleins</term><term>Transfection</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Caspases</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Neocortex</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Apoptosis</term><term>Nerve Tissue Proteins</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Ceramides</term><term>Cysteine Proteinase Inhibitors</term><term>Etoposide</term><term>Staurosporine</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Neocortex</term><term>Neurons</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Humans</term><term>Mutation</term><term>Neuroprotective Agents</term><term>Synucleins</term><term>Transfection</term><term>alpha-Synuclein</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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