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dc.contributor.authorSabirzhanov, B.
dc.contributor.authorMakarevich, O.
dc.contributor.authorBarrett, J.
dc.contributor.authorJackson, I.L.
dc.contributor.authorFaden, A.I.
dc.contributor.authorStoica, B.A.
dc.date.accessioned2020-06-08T20:21:00Z
dc.date.available2020-06-08T20:21:00Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85085398253&doi=10.3390%2fijms21103695&partnerID=40&md5=2ec41806f0bbdbb635e6bdc6345235c4
dc.identifier.urihttp://hdl.handle.net/10713/12989
dc.description.abstractRadiation-induced central nervous system toxicity is a significant risk factor for patients receiving cancer radiotherapy. Surprisingly, the mechanisms responsible for the DNA damage-triggered neuronal cell death following irradiation have yet to be deciphered. Using primary cortical neuronal cultures in vitro, we demonstrated that X-ray exposure induces the mitochondrial pathway of intrinsic apoptosis and that miR-23a-3p plays a significant role in the regulation of this process. Primary cortical neurons exposed to irradiation show the activation of DNA-damage response pathways, including the sequential phosphorylation of ATM kinase, histone H2AX, and p53. This is followed by the p53-dependent up-regulation of the pro-apoptotic Bcl2 family molecules, including the BH3-only molecules PUMA, Noxa, and Bim, leading to mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, which activates caspase-dependent apoptosis. miR-23a-3p, a negative regulator of specific pro-apoptotic Bcl-2 family molecules, is rapidly decreased after neuronal irradiation. By increasing the degradation of PUMA and Noxa mRNAs in the RNA-induced silencing complex (RISC), the administration of the miR-23a-3p mimic inhibits the irradiation-induced up-regulation of Noxa and Puma. These changes result in an attenuation of apoptotic processes such as MOMP, the release of cytochrome c and caspases activation, and a reduction in neuronal cell death. The neuroprotective effects of miR-23a-3p administration may not only involve the direct inhibition of pro-apoptotic Bcl-2 molecules downstream of p53 but also include the attenuation of secondary DNA damage upstream of p53. Importantly, we demonstrated that brain irradiation in vivo results in the down-regulation of miR-23a-3p and the elevation of pro-apoptotic Bcl2-family molecules PUMA, Noxa, and Bax, not only broadly in the cortex and hippocampus, except for Bax, which was up-regulated only in the hippocampus but also selectively in isolated neuronal populations from the irradiated brain. Overall, our data suggest that miR-23a-3p down-regulation contributes to irradiation-induced intrinsic pathways of neuronal apoptosis. These regulated pathways of neurodegeneration may be the target of effective neuroprotective strategies using miR-23a-3p mimics to block their development and increase neuronal survival after irradiation. Copyright 2020 by the authors.en_US
dc.description.sponsorshipThis work was supported by Merit Review Award # 1I01 RX001993 from the United States (U.S.) Department of Veterans Affairs, Rehabilitation Research and Development Service as well as National Institutes of Health (NIH) grants R01 NS091191, R01 NS096002.en_US
dc.description.urihttp://doi.org/10.3390/ijms21103695en_US
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.subjectBimen_US
dc.subjectMicroRNA (miR)en_US
dc.subjectMOMPen_US
dc.subjectNeuronal apoptosisen_US
dc.subjectNoxaen_US
dc.subjectPumaen_US
dc.subjectRadiationen_US
dc.titleDown-regulation of miR-23a-3p mediates irradiation-induced neuronal apoptosisen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/ijms21103695
dc.identifier.pmid32456284


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