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Título

The p53 Arg72Pro single nucleotide polymorphism determines amyloid-ß neurotoxicity upon Cdk5-induced p53 stabilization

AutorLapresa, Rebeca; Bolaños, Juan P.; Almeida, Angeles
Fecha de publicación2016
CitaciónXXXIX Congreso de la SEBBM (2016)
ResumenThe p53 tumor suppressor protein functions as a key regulator of cell apoptosis and has been described to accumulate in affected brain areas from Alzheimer’s disease (AD) patients. However, the role of p53 in AD is controversial. This protein naturally occurs in humans in two functional variants with single nucleotide polymorphism (SNP) resulting in Arg or Pro at residue 72 that modulates the apoptotic activity of the p53 protein. Here, we evaluated the impact of the p53 Arg72Pro SNP on amyloid-ß (Aß)-induced neuronal apoptosis. Exposure of cortical neurons in primary culture to Aß triggered cyclin dependent kinase-5 (Cdk5)-induced p53 phosphorylation and stabilization, leading to mitochondrial dysfunction and neuronal apoptosis, which were prevented by genetic inhibition of Cdk5 and p53. In cortical neurons from humanized Tp53 Arg72Pro knock-in mice, we found that neurons expressing the Arg72-p53 polymorphic variant showed a higher susceptibility to Aß-mediated mitochondrial depolarization and neuronal death when compared with the Pro72-p53 variant. This effect was abrogated by ectopically expressing apoε4 –a well-known major risk factor for AD- but not apoε3 and apoε2. These results indicate that neuronal susceptibility to Aß toxicity is conditioned by the Tp53 Arg72Pro SNP, hence suggesting that this SNP may be considered as a genetic biomarker for AD risk in apoε4 non-carriers.
DescripciónResumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.
URIhttp://hdl.handle.net/10261/157403
Aparece en las colecciones: (IBFG) Comunicaciones congresos
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