The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke

作者：Gomez Sanchez Jose C; Delgado Esteban Maria; Rodriguez Hernandez Irene; Sobrino Tomas; Perez de la Ossa Natalia; Reverte Silvia; Bolanos Juan P; Gonzalez Sarmiento Rogelio; Castillo Jose; Almeida Angeles^*

来源：Journal of Experimental Medicine, 2011, 208(3): 429-437.

DOI：10.1084/jem.20101523

The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg(72)-p53, but not Pro(72)-p53, interacted directly with mitochondria! Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke.

• 出版日期2011-3-14