IRE1α RIDD activity induced under ER stress drives neuronal death by the degradation of 14-3-3 θ mRNA in cortical neurons during glucose deprivation

AbstractAltered protein homeostasis is associated with neurodegenerative diseases and acute brain injury induced under energy depletion conditions such as ischemia. The accumulation of damaged or unfolded proteins triggers the unfolded protein response (UPR), which can act as a homeostatic response or lead to cell death. However, the factors involved in turning and adaptive response into a cell death mechanism are still not well understood. Several mechanisms leading to brain injury induced by severe hypoglycemia have been described but the contribution of the UPR has been poorly studied. Cell responses triggered during both the hypoglycemia and the glucose reinfusion periods can contribute to neuronal death. Therefore, we have investigated the activation dynamics of the PERK and the IRE1α branches of the UPR and their contribution to neuronal death in a model of glucose deprivation (GD) and glucose reintroduction (GR) in cortical neurons. Results show a rapid activation of the PERK/p-eIF2α/ATF4 pathway leading to protein synthesis inhibition during GD, which contributes to neuronal adaptation, however, sustained blockade of protein synthesis during GR promotes neuronal death. On the other hand, IRE1α activation occurs early during GD due to its interaction with BAK/BAX, while ASK1 is recruited to IRE1α activation complex during GR promoting the nuclear translocation of JNK and the upregulation of Chop. Most importantly, results show that IRE1α RNase activity towards its splicing target Xbp1 mRNA occurs late after GR, precluding a homeostatic role. Instead, IRE1α activity during GR drives neuronal death by positively regulating ASK1/JNK activity through the degradation of 14-3-3 θ mRNA, a negative regulator of ASK and an adaptor protein highly expressed in brain, implicated in neuroprotection. Collectively, results describe a novel regulatory mechanism of cell death in neurons, triggered by the downregulation of 14-3-3 θ mRNA induced by the IRE1α branch of the UPR.

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A Concerted Role of Na+—K+—Cl− Cotransporter and Na+/Ca2+ Exchanger in Ischemic Damage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600561 ◽

2007 ◽

Vol 28 (4) ◽

pp. 737-746 ◽

Cited By ~ 24

Author(s):

Jing Luo ◽

Yanping Wang ◽

Hai Chen ◽

Douglas B Kintner ◽

Sam W Cramer ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Mortality Rate ◽

Neuronal Death ◽

Cortical Neurons ◽

Infarct Volume ◽

Glucose Deprivation ◽

Ischemic Damage ◽

Oxygen And Glucose Deprivation

Na+–K+–Cl− cotransporter isoform 1 (NKCC1) and Na+/Ca2+ exchanger isoform 1 (NCX1) were expressed in cortical neurons. Three hours of oxygen and glucose deprivation (OGD) significantly increased expression of full-length NCX1 protein (∼116 kDa), which remained elevated during 1 to 21 h reoxygenation (REOX) and was accompanied with concurrent cleavage of NCX1. Na+/Ca2+ exchanger isoform 1 heterozygous (NCX1+/−) neurons with ∼50% less of NCX1 protein exhibited ∼64% reduction in NCX-mediated Ca2+ influx. Expression of NCX1 and NKCC1 proteins was reduced in double heterozygous (NCX1+/−/NKCC1+/−) neurons. NCX-mediated Ca2+ influx was nearly abolished in these neurons. Three-hour OGD and 21-h REOX caused ∼80% mortality rate in NCX1+/+ neurons and in NCX1+/− neurons. In contrast, NKCC1+/− neurons exhibited ∼45% less cell death. The lowest mortality rate was found in NCX1+/−/NKCC1+/− neurons (∼65% less neuronal death). The increased tolerance to ischemic damage was also observed in NCX1+/−/NKCC1+/− brains after transient cerebral ischemia. NCX1+/−/NKCC1+/− mice had a significantly reduced infarct volume at 24 and 72 h reperfusion. In conclusion, these data suggest that NKCC1 in conjunction with NCX1 plays a role in reperfusion-induced brain injury after ischemia.

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Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice

ASN NEURO ◽

10.1177/1759091420930865 ◽

2020 ◽

Vol 12 ◽

pp. 175909142093086

Author(s):

Laura E. Montroull ◽

Deborah E. Rothbard ◽

Hur D. Kanal ◽

Veera D’Mello ◽

Vincent Dodson ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Neuronal Death ◽

Apoptotic Cell ◽

Neuronal Cell ◽

Adult Brain ◽

Neurotrophin Receptor ◽

Cortical Impact ◽

Impact Injury

The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

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miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

Molecular Brain ◽

10.1186/s13041-019-0501-0 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Xiao Xiao ◽

Youjing Jiang ◽

Weibo Liang ◽

Yanyun Wang ◽

Shuqiang Cao ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Neuronal Death ◽

Sham Group ◽

Ferrous Ion ◽

Post Injury ◽

Regulated Cell Death ◽

Prostaglandin Endoperoxide Synthase ◽

Improved Learning

Abstract Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

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Attenuation of Neuronal Death by NMDA and Oxygen-Glucose Deprivation in Cortical Neurons Maintained in High Glucose

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1999.tb07864.x ◽

1999 ◽

Vol 893 (1 OXIDATIVE/ENE) ◽

pp. 396-399 ◽

Cited By ~ 3

Author(s):

SO YOUNG SEO ◽

EUN YOUNG KIM ◽

HARRIET KIM ◽

ILO JOU ◽

BYOUNG JOO GWAG

Keyword(s):

High Glucose ◽

Neuronal Death ◽

Cortical Neurons ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation

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TRAF2 inhibits TRAIL- and CD95L-induced apoptosis and necroptosis

Cell Death and Disease ◽

10.1038/cddis.2014.404 ◽

2014 ◽

Vol 5 (10) ◽

pp. e1444-e1444 ◽

Cited By ~ 41

Author(s):

I Karl ◽

M Jossberger-Werner ◽

N Schmidt ◽

S Horn ◽

M Goebeler ◽

...

Keyword(s):

Cell Death ◽

Hela Cells ◽

Protein Complexes ◽

Combined Treatment ◽

Death Receptor ◽

Adaptor Protein ◽

Negative Regulator ◽

Interacting Protein ◽

Induced Apoptosis ◽

The Impact

Abstract The relevance of the adaptor protein TNF receptor-associated factor 2 (TRAF2) for signal transduction of the death receptor tumour necrosis factor receptor1 (TNFR1) is well-established. The role of TRAF2 for signalling by CD95 and the TNF-related apoptosis inducing ligand (TRAIL) DRs, however, is only poorly understood. Here, we observed that knockdown (KD) of TRAF2 sensitised keratinocytes for TRAIL- and CD95L-induced apoptosis. Interestingly, while cell death was fully blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) in control cells, TRAF2-depleted keratinocytes were only partly rescued from TRAIL- and CD95L-induced cell death. In line with the idea that the only partially protective effect of zVAD-fmk on TRAIL- and CD95L-treated TRAF2-depleted keratinocytes is due to the induction of necroptosis, combined treatment with zVAD-fmk and the receptor interacting protein 1 (RIP1) inhibitor necrostatin-1 fully rescued these cells. To better understand the impact of TRAF2 levels on RIP1- and RIP3-dependent necroptosis and RIP3-independent apoptosis, we performed experiments in HeLa cells that lack endogenous RIP3 and HeLa cells stably transfected with RIP3. HeLa cells, in which necroptosis has no role, were markedly sensitised to TRAIL-induced caspase-dependent apoptosis by TRAF2 KD. In RIP3-expressing HeLa transfectants, however, KD of TRAF2 also strongly sensitised for TRAIL-induced necroptosis. Noteworthy, priming of keratinocytes with soluble TWEAK, which depletes the cytosolic pool of TRAF2-containing protein complexes, resulted in strong sensitisation for TRAIL-induced necroptosis but had only a very limited effect on TRAIL-induced apoptosis. The necroptotic TRAIL response was not dependent on endogenously produced TNF and TNFR signalling, since blocking TNF by TNFR2-Fc or anti-TNFα had no effect on necroptosis induction. Taken together, we identified TRAF2 not only as a negative regulator of DR-induced apoptosis but in particular also as an antagonist of TRAIL- and CD95L-induced necroptosis.

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OTULIN is a New Target for EA Treatment in Alleviating Brain Injury and The Activation of Glial Cells By Depressing NF-κB Signalling Pathway in Acute Ischaemic Stroke Rats

10.21203/rs.3.rs-153447/v1 ◽

2021 ◽

Author(s):

Hongbei Xu ◽

You Wang ◽

Yong Luo

Keyword(s):

Brain Injury ◽

Ischaemic Stroke ◽

Glial Cells ◽

Acute Ischaemic Stroke ◽

Nuclear Translocation ◽

Infarct Volume ◽

Cerebral Infarct ◽

Signalling Pathway ◽

Negative Regulator ◽

Tnf Α

Abstract Objective: Ovarian tumour domain deubiquitinase with linear linkage specificity (OTULIN), a potent negative regulator of nuclear factor-κB (NF-κB) signalling pathway, exerted strong neuroprotective role following acute ischemic stroke. Electroacupuncture (EA) is an effective adjuvant treatment for reducing brain injury and neuroinflammtion through inhibiting the nuclear translocation of NF-κB p65, while the underlying mechanism remains unclear. This study investigated whether OTULIN was necessary for EA to mitigate brain injury and the activation of glial cells, following by a transient middle cerebral artery occlusion (tMCAO) model in rats.Methods: Acute ischaemic stroke model was established by performing tMCAO surgery in Sprague-Dawley (SD) rats. EA was performed once daily at “Baihui (GV 20)”, “Hegu (LI 4)”, and “Taichong (LR 3)” acupoints. EA’s effect on the spatiotemporal expression of OTULIN in the ischaemic penumbra of cerebral cortex was detected within 7 d after reperfusion. Following gene interference to silence OTULIN expression, the effects of OTULIN on EA neurological deficits, cerebral infarct volume, neuronal damage, the activation of microglia and astrocytes, the contents of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), and the expression of p-IκBa, IκBa and nucleus/cytoplasm NF-κB p65 protein were assessed. Results: EA treatment increased endogenous OTULIN expression, with a peak at 48 h. Enhanced OTULIN was mainly located in neurons, and little OTULIN was detected in microglia as well. OTULIN silencing obviously reversed EA neuroprotection as demonstrated by worsened neurobehavioural performance, cerebral infarct volume and neuronal injury. Besides, the inhibitory effect of EA on NF-κB pathway was also attenuated by enhanced IκBα phosphorylation and NF-κB p65 nuclear translocation. Furthermore, EA partly inhibited the transformation of microglia and astrocytes to from resting states to activated states, and reduced the secretion of TNF-α, IL-1β and IL-6, but this preventive effects were reversed after silencing OTULIN expression. Conclusions: OTULIN provides a new potential therapeutic target for EA to alleviate acute ischaemic stroke induced brain injury and the activation of glial cells, which is related to depression of NF-κB signalling pathway.

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A1 adenosine receptors mediate hypoglycemia-induced neuronal injury

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0320129 ◽

2004 ◽

Vol 32 (1) ◽

pp. 129-144 ◽

Cited By ~ 25

Author(s):

CP Turner ◽

MR Blackburn ◽

SA Rivkees

Keyword(s):

Adenosine Receptors ◽

Neuronal Death ◽

Cortical Neurons ◽

Caspase 3 ◽

Neuronal Injury ◽

Glucose Deprivation ◽

Cellular Mechanisms ◽

Neuronal Viability ◽

Rat Cortical Neurons ◽

A1 Adenosine Receptors

The cellular mechanisms that lead to neuronal death following glucose deprivation are not known, although it is recognized that hypoglycemia can lead to perturbations in intracellular calcium ([Ca2+]i) levels. Recently, activation of A1 adenosine receptors (A1AR) has been shown to alter [Ca2+]i and promote neuronal death. Thus, we examined if A1AR activation contributes to hypoglycemia-induced neuronal injury using rat cortical neurons. First, we observed that hypoglycemia was associated with large increases in neuronal adenosine release. Next, decreased neuronal viability was seen with progressive reduction in glucose concentration (25, 6, 3, 0.75 and 0 mM). Using the calcium-sensitive dye, Fluo-3, we observed both acute and long-term changes in relative [Ca2+]i during hypoglycemic conditions. Demonstrating a role for adenosine in this process, both the loss in neuronal viability and the early changes in [Ca2+]i were reversed by treatment with A1AR antagonists (8-cyclopentyl, 1,3-dipropylxanthine; 9-chloro-2-(2-furyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-amine; and N-cyclopentyl-9-methyladenine). We also found that hypoglycemia induced the expression of the pro-apoptotic enzyme, caspase-3, and that A1AR antagonism reversed hypoglycemia-induced caspase-3 activity. Collectively, these data show that hypoglycemia induces A1ARs activation leading to alterations in [Ca2+]i, which plays a prominent role in leading to hypoglycemia-induced neuronal death.

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Autophagy fails to prevent glucose deprivation/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons

Cell Death and Disease ◽

10.1038/cddis.2017.299 ◽

2017 ◽

Vol 8 (6) ◽

pp. e2911-e2911 ◽

Cited By ~ 21

Author(s):

Cristian Gerónimo-Olvera ◽

Teresa Montiel ◽

Ruth Rincon-Heredia ◽

Susana Castro-Obregón ◽

Lourdes Massieu

Keyword(s):

Neuronal Death ◽

Cortical Neurons ◽

Glucose Deprivation ◽

Lysosomal Dysfunction

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Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices

Glia ◽

10.1002/glia.22478 ◽

2013 ◽

Vol 61 (5) ◽

pp. 813-824 ◽

Cited By ~ 86

Author(s):

Sylvie Girard ◽

David Brough ◽

Gloria Lopez-Castejon ◽

James Giles ◽

Nancy J. Rothwell ◽

...

Keyword(s):

Cell Death ◽

Brain Injury ◽

Brain Slices ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Organotypic Brain Slices

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BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms222111395 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11395

Author(s):

So Yoon Ahn ◽

Dong Kyung Sung ◽

Yun Sil Chang ◽

Se In Sung ◽

Young Eun Kim ◽

...

Keyword(s):

Stem Cells ◽

Cell Death ◽

Mesenchymal Stem Cells ◽

Brain Injury ◽

Therapeutic Efficacy ◽

Inflammatory Responses ◽

Apoptotic Cell ◽

Glucose Deprivation

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

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