title: Direct α-synuclein promoter transactivation by the tumor suppressor p53.
abstract: BACKGROUND
  Parkinson's disease (PD) is a motor disease associated with the degeneration of dopaminergic neurons of the substantia nigra pars compacta. p53 is a major neuronal pro-apoptotic factor that is at the center of gravity of multiple physiological and pathological cascades, some of which implying several key PD-linked proteins. Since p53 is up-regulated in PD-affected brain, we have examined its ability to regulate the transcription of α-synuclein, a key protein that accumulates in PD-related Lewy bodies.
  
  
  RESULTS
  We show that pharmacological and genetic up-regulation of p53 expression lead to a strong increase of α-synuclein protein, promoter activity and mRNA levels. Several lines of evidence indicate that this transcriptional control is due to the DNA-binding properties of p53. Firstly, p53 DNA-binding dead mutations abolish p53 regulation of α-synuclein. Secondly, the deletion of p53 responsive element from α-synuclein promoter abrogates p53-mediated α-synuclein regulation. Thirdly, gel shift and chromatin immunoprecipitation studies indicate that p53 interacts physically with α-synuclein promoter both in vitro and in a physiological context. Furthermore, we show that the depletion of endogenous p53 in cells as well as in knockout mice down-regulates α-synuclein transcription.
  
  
  CONCLUSIONS
  Overall, we have identified α-synuclein as a new transcriptional target of p53 and delineated a cellular mechanism feeding the accumulation of toxic aggregated α-synuclein in PD. This original α-syn regulatory mechanism may be central to PD-related cell death and may lead to novel opportunities to design alternative neuroprotective strategies in PD.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled "Fondation pour la Recherche Médicale" and "Laboratory of Excellence (LABEX) Distalz", 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Duplan
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled "Fondation pour la Recherche Médicale" and "Laboratory of Excellence (LABEX) Distalz", 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled "Fondation pour la Recherche Médicale" and "Laboratory of Excellence (LABEX) Distalz", 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France. checler@ipmc.cnrs.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled "Fondation pour la Recherche Médicale" and "Laboratory of Excellence (LABEX) Distalz", 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France. acosta@ipmc.cnrs.fr.
authors.forename: Cristine
authors.initials: C
authors.lastname: Alves da Costa
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D016631:Lewy Bodies / Q000378:metabolism*; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C497605:Snca protein, mouse; D016159:Tumor Suppressor Protein p53; D051844:alpha-Synuclein
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