Department of Neurology, University Hospital of Salamanca, 37007 Salamanca, Spain.
J Exp Med. 2011 Mar 14;208(3):429-37. doi: 10.1084/jem.20101523. Epub 2011 Feb 28.
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 mitochondrial 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.
中风后的功能结果是不可预测的；它不能通过入院时的临床图像准确预测。缺血半影区和血肿周围凋亡神经元的存在可能与预后不良有关，但高度可变的中风结果是否反映了对细胞凋亡的遗传易感性差异尚不清楚。p53 肿瘤抑制蛋白是细胞凋亡的重要转录调节因子，在人类中自然存在两种变体，单核苷酸多态性导致第 72 位残基的精氨酸或脯氨酸。我们表明，无论是缺血性中风还是出血性中风后功能结果不良都与 Arg/Arg 基因型有关。这种基因型也与缺血性中风中的早期神经功能恶化以及脑出血中的残余腔体积增加有关。在原代培养的神经元中，Arg(72)-p53 而不是 Pro(72)-p53 与线粒体 Bcl-xL 直接相互作用并激活内在凋亡途径，增加对缺血诱导的凋亡性细胞死亡的易感性。这些结果表明，Tp53 Arg/Arg 基因型决定了神经元对细胞凋亡的易感性，可以被认为是预测中风后功能结果不良的遗传标志物。
