Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson's disease.
Identifieur interne : 001106 ( PubMed/Curation ); précédent : 001105; suivant : 001107Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson's disease.
Auteurs : Cristine Alves Da Costa [France] ; Erwan Paitel ; Bruno Vincent ; Frédéric CheclerSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2002.
English descriptors
- KwdEn :
- Apoptosis (drug effects), Apoptosis (physiology), Caspase 3, Caspases (metabolism), Cell Line, Cells, Cultured, Humans, Kidney, Kinetics, Models, Biological, Nerve Tissue Proteins (genetics), Nerve Tissue Proteins (physiology), Neurons (cytology), Neurons (drug effects), Neurons (physiology), Oxidopamine (pharmacology), Parkinson Disease (pathology), Parkinson Disease (physiopathology), Recombinant Proteins (metabolism), Synucleins, Transfection, Tumor Suppressor Protein p53 (physiology), alpha-Synuclein.
- MESH :
- chemical , genetics : Nerve Tissue Proteins.
- chemical , metabolism : Caspases, Recombinant Proteins.
- chemical , pharmacology : Oxidopamine.
- chemical , physiology : Nerve Tissue Proteins, Tumor Suppressor Protein p53.
- chemical : Caspase 3, Synucleins, alpha-Synuclein.
- cytology : Neurons.
- drug effects : Apoptosis, Neurons.
- pathology : Parkinson Disease.
- physiology : Apoptosis, Neurons.
- physiopathology : Parkinson Disease.
- Cell Line, Cells, Cultured, Humans, Kidney, Kinetics, Models, Biological, Transfection.
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.
DOI: 10.1074/jbc.M207825200
PubMed: 12397073
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Abolishment by 6-hydroxydopamine and implication for Parkinson's disease.</title><author><name sortKey="Alves Da Costa, Cristine" sort="Alves Da Costa, Cristine" uniqKey="Alves Da Costa C" first="Cristine" last="Alves Da Costa">Cristine Alves Da Costa</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne</wicri:regionArea></affiliation></author><author><name sortKey="Paitel, Erwan" sort="Paitel, Erwan" uniqKey="Paitel E" first="Erwan" last="Paitel">Erwan Paitel</name></author><author><name sortKey="Vincent, Bruno" sort="Vincent, Bruno" uniqKey="Vincent B" first="Bruno" last="Vincent">Bruno Vincent</name></author><author><name sortKey="Checler, Frederic" sort="Checler, Frederic" uniqKey="Checler F" first="Frédéric" last="Checler">Frédéric Checler</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2002">2002</date><idno type="RBID">pubmed:12397073</idno><idno type="pmid">12397073</idno><idno type="doi">10.1074/jbc.M207825200</idno><idno type="wicri:Area/PubMed/Corpus">001147</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001147</idno><idno type="wicri:Area/PubMed/Curation">001106</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001106</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. 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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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">12397073</PMID><DateCreated><Year>2002</Year><Month>12</Month><Day>23</Day></DateCreated><DateCompleted><Year>2003</Year><Month>02</Month><Day>27</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0021-9258</ISSN><JournalIssue CitedMedium="Print"><Volume>277</Volume><Issue>52</Issue><PubDate><Year>2002</Year><Month>Dec</Month><Day>27</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J. Biol. 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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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Alves Da Costa</LastName><ForeName>Cristine</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Paitel</LastName><ForeName>Erwan</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Vincent</LastName><ForeName>Bruno</ForeName><Initials>B</Initials></Author><Author 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