Abstract
Radiation-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.
Highlights
Radiation therapy is one of the most important interventions targeting central nervous system tumors
Expression of Pro-Apoptotic Members of B cell leukemia/lymphoma 2 (Bcl-2) Family is Upregulated, and miR-23a-3p is Downregulated in the Cortex, Hippocampus, and Purified Neurons after Mouse Brain Irradiation
(1) First, we demonstrate that irradiation triggers intrinsic apoptosis in primary neurons in vitro including the activation of DNA-damage responses, followed by p53-dependent up-regulation of the pro-apoptotic Bcl-2 family molecules PUMA, Noxa, and Bim, mitochondrial outer membrane permeabilization, and the release of cytochrome c, which activates intrinsic caspase-dependent apoptosis
Summary
Radiation therapy is one of the most important interventions targeting central nervous system tumors. Studies have shown that IR induces DNA damage and activates neuronal apoptotic pathways, leading to neuronal loss [8,9,10]. Agents such as valproic acid [11] and lithium [12,13] may down-regulate the expression of pro-apoptotic Bcl-2 genes and attenuate IR-induced neuronal apoptosis, improving cognitive performance. Neuroprotection could be an effective strategy to prevent the development of neurocognitive deficits after brain irradiation This approach would require a much better understanding of the molecular mechanisms involved in neuronal apoptosis after ionizing radiation and their key regulators than is currently available [15]
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