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 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 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.

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 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

scholarly journals The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina

2021 ◽  
Vol 22 (16) ◽  
pp. 9050
Author(s):  
Toshiyuki Oshitari
Keyword(s):  
Cell Death ◽  
Diabetic Retinopathy ◽  
Diabetic Neuropathy ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Axon Degeneration ◽  
Diabetic Patients ◽  
Therapeutic Approaches

Diabetic retinopathy is a major retinal disease and a leading cause of blindness in the world. Diabetic retinopathy is a neurovascular disease that is associated with disturbances of the interdependent relationship of cells composed of the neurovascular units, i.e., neurons, glial cells, and vascular cells. An impairment of these neurovascular units causes both neuronal and vascular abnormalities in diabetic retinopathy. More specifically, neuronal abnormalities including neuronal cell death and axon degeneration are irreversible changes that are directly related to the vision reduction in diabetic patients. Thus, establishment of neuroprotective and regenerative therapies for diabetic neuropathy in the retina is an emergent task for preventing the blindness of patients with diabetic retinopathy. This review focuses on the pathogenesis of the neuronal abnormalities in diabetic retina including glial abnormalities, neuronal cell death, and axon degeneration. The possible molecular cell death pathways and intrinsic survival and regenerative pathways are also described. In addition, therapeutic approaches for diabetic neuropathy in the retina both in vitro and in vivo are presented. This review should be helpful for providing clues to overcome the barriers for establishing neuroprotection and regeneration of diabetic neuropathy in the retina.

DJ-1 promotes the proteasomal degradation of Fis1: implications of DJ-1 in neuronal protection

2012 ◽  
Vol 447 (2) ◽  
pp. 261-269 ◽  
Author(s):  
Qiang Zhang ◽  
Junbing Wu ◽  
Rong Wu ◽  
Jun Ma ◽  
Guiping Du ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Ring Finger ◽  
E3 Ligase ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Proteasomal Degradation ◽  
Antioxidant Property ◽  
Mitochondrial Outer Membrane ◽  
Neuronal Protection

Mutations in DJ-1/PARK7 (Parkinson protein 7) have been identified as a cause of autosomal-recessive PD (Parkinson's disease) and the antioxidant property of DJ-1 has been shown to be involved in the regulation of mitochondrial function and neuronal cell survival. In the present study, we first found that the DJ-1 transgene mitigated MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced DA (dopamine) neuron cell death and cell loss. We then observed that the protein levels of DJ-1 were significantly decreased, whereas levels of Fis1 [fission 1 (mitochondrial outer membrane) homologue] were noticeably increased in the striatum of MPTP-treated mice. In addition to our identification of RNF5 (RING-finger protein-5) as an E3-ligase for Fis1 ubiquitination, we demonstrated the involvement of the DJ-1/Akt/RNF5 signalling pathway in the regulation of Fis1 proteasomal degradation. In other experiments, we found that Akt1 enhances the mitochondrial translocation and E3-ligase activity of RNF5, leading to Fis1 degradation. Together, the identification of Fis1 degradation by DJ-1 signalling in the regulation of oxidative stress-induced neuronal cell death supplies a novel mechanism of DJ-1 in neuronal protection with the implication of DJ-1 in a potential therapeutic avenue for PD.

scholarly journals Prostaglandin E2 Type 1 Receptors Contribute to Neuronal Apoptosis after Transient Forebrain Ischemia

2013 ◽  
Vol 33 (8) ◽  
pp. 1207-1214 ◽  
Author(s):  
Munehisa Shimamura ◽  
Ping Zhou ◽  
Barbara Casolla ◽  
Liping Qian ◽  
Carmen Capone ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Prostaglandin E ◽  
Pathophysiological Mechanism ◽  
Forebrain Ischemia ◽  
Transient Forebrain Ischemia

Cyclooxygenase-2-derived prostaglandin E2 (PGE2) contributes to excitotoxic and ischemic neuronal cell death by engaging neuronal PGE2 type 1 receptors (EP1R). Our previous studies have shown that EP1R signaling resulted in disturbances of intracellular Ca2 + homeostasis and suppression of the pro-survival protein kinase AKT. The aim of this study was to investigate whether these pathophysiological mechanism have a role in the neuronal cell death after transient forebrain ischemia. Mice were subjected to ischemia/reperfusion by bilateral common carotid artery occlusion. Hippocampal cornu ammonis area 1 (CA1) neuronal cell death was determined 5 days after reperfusion. Animals treated with the EP1R antagonist SC51089 or EP1R-deficient mice (EP1 –/–) showed significantly less neuronal injury as compared to vehicle-treated wild-type controls. Benefits of EP1R blockage were still evident 14 days after injury. Better neuronal survival was correlated with reduced neuronal caspase-3 activity and decreased nuclear translocation of the apoptosis-inducing factor. Neuroprotection could be reverted by intracerebroventricular administration of the phosphoinositide 3-kinase inhibitor LY294002 and was not further increased by the calcineurin inhibitor FK506. These data implicate EP1R in postischemic neuronal apoptosis possibly by facilitating AKT inhibition.

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