scholarly journals Down-Regulation of miR-23a-3p Mediates Irradiation-Induced Neuronal Apoptosis

2020 ◽  
Vol 21 (10) ◽  
pp. 3695 ◽  
Author(s):  
Boris Sabirzhanov ◽  
Oleg Makarevich ◽  
James Barrett ◽  
Isabel L. Jackson ◽  
Alan I. Faden ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cytochrome C ◽  
Neuronal Apoptosis ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Negative Regulator ◽  
Down Regulation ◽  
Bcl2 Family ◽  
Mitochondrial Outer Membrane Permeabilization

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.

scholarly journals Mithramycin selectively attenuates DNA-damage-induced neuronal cell death

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Oleg Makarevich ◽  
Boris Sabirzhanov ◽  
Taryn G. Aubrecht ◽  
Ethan P. Glaser ◽  
Brian M. Polster ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Primary Neurons ◽  
Intrinsic Apoptosis ◽  
Dna Breaks ◽  
Mitochondrial Outer Membrane Permeabilization

Abstract DNA damage triggers cell death mechanisms contributing to neuronal loss and cognitive decline in neurological disorders, including traumatic brain injury (TBI), and as a side effect of chemotherapy. Mithramycin, which competitively targets chromatin-binding sites of specificity protein 1 (Sp1), was used to examine previously unexplored neuronal cell death regulatory mechanisms via rat primary neurons in vitro and after TBI in mice (males). In primary neurons exposed to DNA-damage-inducing chemotherapy drugs in vitro we showed that DNA breaks sequentially initiate DNA-damage responses, including phosphorylation of ATM, H2AX and tumor protein 53 (p53), transcriptional activation of pro-apoptotic BH3-only proteins, and mitochondrial outer membrane permeabilization (MOMP), activating caspase-dependent and caspase-independent intrinsic apoptosis. Mithramycin was highly neuroprotective in DNA-damage-dependent neuronal cell death, inhibiting chemotherapeutic-induced cell death cascades downstream of ATM and p53 phosphorylation/activation but upstream of p53-induced expression of pro-apoptotic molecules. Mithramycin reduced neuronal upregulation of BH3-only proteins and mitochondrial dysfunction, attenuated caspase-3/7 activation and caspase substrates’ cleavage, and limited c-Jun activation. Chromatin immunoprecipitation indicated that mithramycin attenuates Sp1 binding to pro-apoptotic gene promoters without altering p53 binding suggesting it acts by removing cofactors required for p53 transactivation. In contrast, the DNA-damage-independent neuronal death models displayed caspase initiation in the absence of p53/BH3 activation and were not protected even when mithramycin reduced caspase activation. Interestingly, experimental TBI triggers a multiplicity of neuronal death mechanisms. Although markers of DNA-damage/p53-dependent intrinsic apoptosis are detected acutely in the injured cortex and are attenuated by mithramycin, these processes may play a reduced role in early neuronal death after TBI, as caspase-dependent mechanisms are repressed in mature neurons while other, mithramycin-resistant mechanisms are active. Our data suggest that Sp1 is required for p53-mediated transactivation of neuronal pro-apoptotic molecules and that mithramycin may attenuate neuronal cell death in conditions predominantly involving DNA-damage-induced p53-dependent intrinsic apoptosis.

scholarly journals Neuronal cell life, death, and axonal degeneration as regulated by the BCL-2 family proteins

2020 ◽  
Vol 28 (1) ◽  
pp. 108-122
Author(s):  
James M. Pemberton ◽  
Justin P. Pogmore ◽  
David W. Andrews
Keyword(s):  
Cell Death ◽  
Neuronal Apoptosis ◽  
Axonal Degeneration ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Axon Degeneration ◽  
Mitochondrial Outer Membrane ◽  
Future Research ◽  
System Disease ◽  
Family Protein

AbstractAxonal degeneration and neuronal cell death are fundamental processes in development and contribute to the pathology of neurological disease in adults. Both processes are regulated by BCL-2 family proteins which orchestrate the permeabilization of the mitochondrial outer membrane (MOM). MOM permeabilization (MOMP) results in the activation of pro-apoptotic molecules that commit neurons to either die or degenerate. With the success of small-molecule inhibitors targeting anti-apoptotic BCL-2 proteins for the treatment of lymphoma, we can now envision the use of inhibitors of apoptosis with exquisite selectivity for BCL-2 family protein regulation of neuronal apoptosis in the treatment of nervous system disease. Critical to this development is deciphering which subset of proteins is required for neuronal apoptosis and axon degeneration, and how these two different outcomes are separately regulated. Moreover, noncanonical BCL-2 family protein functions unrelated to the regulation of MOMP, including impacting necroptosis and other modes of cell death may reveal additional potential targets and/or confounders. This review highlights our current understanding of BCL-2 family mediated neuronal cell death and axon degeneration, while identifying future research questions to be resolved to enable regulating neuronal survival pharmacologically.

scholarly journals Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

2017 ◽  
Vol 43 (5) ◽  
pp. 1866-1879 ◽  
Author(s):  
Peng Li ◽  
Kun Ma ◽  
Hao-Yu Wu ◽  
Yan-Ping Wu ◽  
Bai-Xiang Li
Keyword(s):  
Cell Death ◽  
Neuronal Apoptosis ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Green Tea Polyphenols ◽  
Key Factors ◽  
Related Proteins ◽  
Catabolic Process ◽  
Plant Compounds

Background/Aims: Atrazine (ATR) is a broad-spectrum herbicide in wide use around the world. However, ATR is neurotoxic and can cause cell death in dopaminergic neurons, leading to neurodegenerative disorders. Autophagy is the basic cellular catabolic process involving the degradation of proteins and damaged organelles. Studies have shown that certain plant compounds can induce autophagy and prevent neuronal cell death. This prompted us to investigate plant compounds that might reduce the neurotoxic effects of ATR. Methods: By CCK-8 and flow cytometry, we tested the ability of five candidate compounds—isoflavones, resveratrol, quercetin, curcumin, and green tea polyphenols—to protect cells from ATR. Changes in the expression of tyrosine hydroxylase (TH) and brain-expressed X-linked 2 (BEX2), autophagy-related proteins and key factors in mTOR signaling, were detected by Western blotting. Results: Isoflavones had the strongest activity against ATR-induced neuronal apoptosis. ATR reduced the expression of TH and BEX2, whereas isoflavones increased TH and BEX2 expression. In addition, ATR inhibited autophagy, whereas isoflavones induced autophagy through the accumulation of LC3-II and decreased expression of p62; this effect was abolished by 3-methyladenine (3-MA). Furthermore, BEX2 siRNA abolished isoflavone-mediated autophagy and neuroprotection in vitro. Conclusion: Isoflavones activate BEX2-dependent autophagy, protecting against ATR-induced neuronal apoptosis.

Oxidative stress-induced CREB upregulation promotes DNA damage repair prior to neuronal cell death protection

2016 ◽  
Vol 425 (1-2) ◽  
pp. 9-24 ◽  
Author(s):  
Nicolás Pregi ◽  
Laura María Belluscio ◽  
Bruno Gabriel Berardino ◽  
Daniela Susana Castillo ◽  
Eduardo Tomás Cánepa
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Damage Repair ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Damage Repair

scholarly journals Dpp and Hedgehog promote the glial response to neuronal apoptosis in the developing Drosophila visual system

PLoS Biology ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. e3001367
Author(s):  
Sergio B. Velarde ◽  
Alvaro Quevedo ◽  
Carlos Estella ◽  
Antonio Baonza
Keyword(s):  
Cell Death ◽  
Nervous System ◽  
Glial Cell ◽  
Glial Cells ◽  
Neuronal Apoptosis ◽  
Morphological Changes ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Jnk Pathway ◽  
Glial Cell Proliferation

Damage in the nervous system induces a stereotypical response that is mediated by glial cells. Here, we use the eye disc of Drosophila melanogaster as a model to explore the mechanisms involved in promoting glial cell response after neuronal cell death induction. We demonstrate that these cells rapidly respond to neuronal apoptosis by increasing in number and undergoing morphological changes, which will ultimately grant them phagocytic abilities. We found that this glial response is controlled by the activity of Decapentaplegic (Dpp) and Hedgehog (Hh) signalling pathways. These pathways are activated after cell death induction, and their functions are necessary to induce glial cell proliferation and migration to the eye discs. The latter of these 2 processes depend on the function of the c-Jun N-terminal kinase (JNK) pathway, which is activated by Dpp signalling. We also present evidence that a similar mechanism controls glial response upon apoptosis induction in the leg discs, suggesting that our results uncover a mechanism that might be involved in controlling glial cells response to neuronal cell death in different regions of the peripheral nervous system (PNS).

scholarly journals Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

2020 ◽  
Vol 21 (15) ◽  
pp. 5239 ◽  
Author(s):  
Boris Sabirzhanov ◽  
Oleg Makarevich ◽  
James P. Barrett ◽  
Isabel L. Jackson ◽  
Ethan P. Glaser ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Intrinsic Apoptosis ◽  
In Vivo Models ◽  
Neuroprotective Strategy ◽  
Radiation Induced

Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21WAF1/Cip1. These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.

Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and neuronal cell death

2006 ◽  
Vol 41 (5) ◽  
pp. 748-756 ◽  
Author(s):  
Shinji Oikawa ◽  
Iwao Hirosawa ◽  
Saeko Tada-Oikawa ◽  
Ayako Furukawa ◽  
Kaoru Nishiura ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Oxidative Dna Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell

scholarly journals 314 S1P Signaling in Neuronal Apoptosis; Links to Resistance and Vulnerability to Ischemic-Induced Neuronal Cell Death

Neurosurgery ◽  
2018 ◽  
Vol 65 (CN_suppl_1) ◽  
pp. 127-127
Author(s):  
Sherif Rashad ◽  
Kuniyasu Niizuma ◽  
Mika Sato-Maeda ◽  
Daisuke Saigusa ◽  
Teiji Tominaga
Keyword(s):  
Cell Death ◽  
Neuronal Apoptosis ◽  
Neuronal Cell Death ◽  
Neuronal Cell

IRON ENHANCEMENT OF OXIDATIVE DNA DAMAGE AND NEURONAL CELL DEATH INDUCED BY SALSOLINOL

2002 ◽  
Vol 65 (5-6) ◽  
pp. 473-488 ◽  
Author(s):  
Young-Joon Surh ◽  
Youn-Joo Jung ◽  
Jung-Hee Jang ◽  
Jeong-Sang Lee ◽  
Hye-Ran Yoon
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Oxidative Dna Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell
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