The Neuronal Ischemic Tolerance Is Conditioned by the Tp53 Arg72Pro Polymorphism

Abstract

Cerebral preconditioning (PC) confers endogenous brain protection after stroke. Ischemic stroke patients with a prior transient ischemic attack (TIA) may potentially be in a preconditioned state. Although PC has been associated with the activation of pro-survival signals, the mechanism by which preconditioning confers neuroprotection is not yet fully clarified. Recently, we have described that PC-mediated neuroprotection against ischemic insult is promoted by p53 destabilization, which is mediated by its main regulator MDM2. Moreover, we have previously described that the human Tp53 Arg72Pro single nucleotide polymorphism (SNP) controls susceptibility to ischemia-induced neuronal apoptosis and governs the functional outcome of patients after stroke. Here, we studied the contribution of the human Tp53 Arg72Pro SNP on PC-induced neuroprotection after ischemia. Our results showed that cortical neurons expressing the Pro72-p53 variant exhibited higher PC-mediated neuroprotection as compared with Arg72-p53 neurons. PC prevented ischemia-induced nuclear and cytosolic p53 stabilization in Pro72-p53 neurons. However, PC failed to prevent mitochondrial p53 stabilization, which occurs in Arg72-p53 neurons after ischemia. Furthermore, PC promoted neuroprotection against ischemia by controlling the p53/active caspase-3 pathway in Pro72-p53, but not in Arg72-p53 neurons. Finally, we found that good prognosis associated to TIA within 1 month prior to ischemic stroke was restricted to patients harboring the Pro72 allele. Our findings demonstrate that the Tp53 Arg72Pro SNP controls PC-promoted neuroprotection against a subsequent ischemic insult by modulating mitochondrial p53 stabilization and then modulates TIA-induced ischemic tolerance.

Interactions among variants in P53 apoptotic pathway genes are associated with neurologic deterioration and functional outcome after acute ischemic stroke

“…Human P 53 Arg72Pro (rs1042522) SNP controls susceptibility to ischemia‐induced neuronal apoptosis and the functional outcome after stroke (Gomez‐Sanchez et al, 2011). P 53 rs1042522 SNP can condition neuronal ischemic tolerance by modulating mitochondrial p53 stabilization (Ramos‐Araque et al, 2018). MMP‐9 polymorphisms regulate the transcription of MMP‐9 protein and are associated with increased IS or cancer risk and hemorrhagic transformation of IS (Yuan et al, 2013; Zhang, Cao, Xu, Li, & Xu, 2015; Zhu et al, 2018).…”

Mitochondrial–nuclear p53 trafficking controls neuronal susceptibility in stroke

“…The impact of genetic susceptibility to apoptosis, and specifically p53‐related mutations, has also proven to be crucial in stroke prognosis 4,30,42,59,66 . Several SNP and sequence variations at the human Tp53 gene have been described so far.…”

“…This SNP has been associated with increased risk of several types of cancer and a decrease in apoptotic and DNA repair capacity in immortalized cell lines 68 . Although there is no evidence linking the Ins16bp SNP to reduced neuronal apoptosis in stroke, 4 a functional polymorphism in its close proximity, the coding Arg72Pro SNP (rs1042522) in exon 4 of Tp53 , has indeed proven to modulate neuronal apoptosis and functional prognosis after stroke 4,66 …”

“…This fact is important in ischemic situations, which promote p53 stabilization and subsequent p53‐dependent apoptosis. However, this is also relevant to induce neuroprotection and ischemic tolerance in preconditioning models 66 . While ischemic preconditioning prevented nuclear and cytosolic stabilization of Pro72‐p53, this effect was not observed in mitochondrial Arg72‐p53‐expressing neurons, which suffer neuronal apoptosis and caspase‐3 activation.…”

“…While ischemic preconditioning prevented nuclear and cytosolic stabilization of Pro72‐p53, this effect was not observed in mitochondrial Arg72‐p53‐expressing neurons, which suffer neuronal apoptosis and caspase‐3 activation. Likewise, Arg72Pro SNP was recently evidenced as a noninvasive biomarker to predict functional prognosis and ischemic tolerance in patients who have experienced a transient ischemic attack 66 …”