The Neuronal Ischemic Tolerance Is Conditioned by the Tp53 Arg72Pro Polymorphism

التفاصيل البيبلوغرافية
العنوان: The Neuronal Ischemic Tolerance Is Conditioned by the Tp53 Arg72Pro Polymorphism
المؤلفون: Francisco Purroy, Elisa Cortijo Garcia, Cristina Rodríguez, Angeles Almeida, Mercedes de Lera Alfonso, Mercedes Sánchez Barba, Rebeca Vecino, Laura Colàs-Campàs, Maria Delgado-Esteban, María E. Ramos-Araque, Juan F. Arenillas
المساهمون: Instituto de Salud Carlos III, Junta de Castilla y León, European Commission, Ministerio de Educación, Cultura y Deporte (España), Delgado-Esteban, María [0000-0002-6205-6611], Delgado-Esteban, María
المصدر: Translational Stroke Research
Digital.CSIC. Repositorio Institucional del CSIC
instname
Repositorio Abierto de la UdL
Universitad de Lleida
Recercat. Dipósit de la Recerca de Catalunya
سنة النشر: 2019
مصطلحات موضوعية: 0301 basic medicine, Male, Neurology, Regulator, Endogeny, Apoptosis, Pharmacology, Brain Ischemia, Membrane Potentials, Cohort Studies, Mice, 0302 clinical medicine, Tp53 Arg72Pro polymorphism, Excitatory Amino Acid Agonists, Ischemic Preconditioning, Transient ischemic attack, Stroke, Cells, Cultured, Aged, 80 and over, Cerebral Cortex, Neurons, biology, Caspase 3, General Neuroscience, Middle Aged, Cell Hypoxia, Neuroprotection, Mdm2, Original Article, Female, Cardiology and Cardiovascular Medicine, Microtubule-Associated Proteins, Subcellular Fractions, medicine.medical_specialty, N-Methylaspartate, Proline, Ischemia, Single-nucleotide polymorphism, Preconditioning, Arginine, Polymorphism, Single Nucleotide, Electron Transport Complex IV, 03 medical and health sciences, medicine, Animals, Humans, cardiovascular diseases, Aged, business.industry, medicine.disease, Embryo, Mammalian, Ischemic tolerance, 030104 developmental biology, Glucose, biology.protein, Neurology (clinical), Tumor Suppressor Protein p53, business, 030217 neurology & neurosurgery
الوصف: 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.
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).
تدمد: 1868-4483
DOI: 10.1007/s12975-018-0631-1
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5047880c6e40935545e7f818f1f38397Test
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....5047880c6e40935545e7f818f1f38397
قاعدة البيانات: OpenAIRE
الوصف
تدمد:18684483
DOI:10.1007/s12975-018-0631-1