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Títol:
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The neuronal ischemic tolerance is conditioned by the Tp53 Arg72Pro polymorphism
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Autor/a:
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Ramos-Araque, Maria E.; Rodriguez, Cristina; Vecino, Rebeca; Cortijo Garcia, Elisa; Lera Alfonso, Mercedes de; Sanchez Barba, Mercedes; Colàs Campàs, Laura; Purroy Garcia, Francisco; Arenillas, Juan F.; Almeida, Angeles; Delgado-Esteban, Maria
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Notes:
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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 prosurvival
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 regulatorMDM2. 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 bymodulatingmitochondrial p53 stabilization and then modulates TIA-induced ischemic tolerance.
This work was funded by The Instituto de Salud Carlos III grants CP14/00010 (M.D.-E.); PI15/00473 and RD12/0014/ 0007 (A.A.); CM14/00096 (ME.R.-A.); RD16/0019/0018 (C.R.); and Junta de Castilla y Leon grant BIO/SA35/15 (M.D.-E.), and the European Regional Development Fund (R.V.) was funded by the FPU program (Ministerio de Educación). |
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Matèries:
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-Ischemic tolerance
-Preconditioning
-Tp53 Arg72Pro polymorphism
-Neuroprotection |
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Drets:
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cc-by (c) Ramos-Araque et al., 2018
http://creativecommons.org/licenses/by/4.0/
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Tipus de document:
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article
publishedVersion |
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Publicat per:
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Springer Verlag
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