Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke
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ABSTRACT:
SUBMITTER: Fuqi Mei
PROVIDER: S-SCDT-10_1038-S44321-025-00206-6 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:ObjectiveProinflammatory necroptosis is the main pathological mechanism of ischemic stroke. Homer scaffolding protein 1 (Homer1) is a postsynaptic scaffolding protein that exerts anti-inflammatory effects in most central nervous system diseases. However, the relationship between Homer1 and proinflammatory necroptosis in ischemic stroke remains unclear.AimThis study aimed to investigate the role of Homer1 in ischemia-induced necroptosis.MethodsC57BL/6 mice were used to establish a model of permanent middle cerebral artery occlusion model (pMCAO). Homer1 knockdown mice were generated using adeno-associated virus (AAV) infection to explore the role of Homer1 and its impact on necroptosis in pMCAO. Finally, Homer1 protein was stereotaxically injected into the ischemic cortex of Homer1flox/flox/Nestin-Cre +/- mice, and the efficacy of Homer1 was investigated using behavioral assays and molecular biological assays to explore potential mechanisms.ResultsHomer1 expression peaked at 8 h in the ischemic penumbral cortex after pMCAO and colocalized with neurons. Homer1 knockdown promoted neuronal death by enhancing necroptotic signaling pathways and aggravating ischemic brain damage in mice. Furthermore, the knockdown of Homer1 enhanced the expression of proinflammatory cytokines. Moreover, injection of Homer1 protein reduced necroptosis-induced brain injury inhibited the expression of proinflammatory factors, and ameliorated the outcomes in the Homer1flox/flox/Nestin-Cre+/- mice after pMCAO.ConclusionsHomer1 ameliorates ischemic stroke by inhibiting necroptosis-induced neuronal damage and neuroinflammation. These data suggested that Homer1 is a novel regulator of neuronal death and neuroinflammation.
| S-EPMC10776472 | biostudies-literature
Project description:Neonatal encephalopathy (NE) caused by hypoxia-ischemia (HI) affects around 1 per 1000 term newborns and is the leading cause of acquired brain injury and neurodisability. Despite the use of hypothermia (HT) as a standard of care, the incidence of NE and its devastating outcomes remains a major issue. Ongoing research surrounding add-on neuroprotective strategies against NE is important as HT effects are limited, leaving 50% of treated patients with neurological sequelae. Little is known about the interaction between necroptotic blockade and HT in neonatal HI. Using a preclinical Lewis rat model of term human NE induced by HI, we showed a neuroprotective effect of Necrostatin-1 (Nec-1: a compound blocking necroptosis) in combination with HT. The beneficial effect of Nec-1 added to HT against NE injuries was observed at the mechanistic level on both pMLKL and TNF-α, and at the anatomical level on brain volume loss visualized by magnetic resonance imaging (MRI). HT alone showed no effect on activated necroptotic effectors and did not preserve the brain MRI volume. This study opens new avenues of research to understand better the specific cell death mechanisms of brain injuries as well as the potential use of new therapeutics targeting the necroptosis pathway.
| S-EPMC9687213 | biostudies-literature
Project description:Early imaging-based detection of acute ischemic stroke (AIS) has improved in the era of reperfusion therapy. Despite of this, prognosis of outcome after AIS remains a challenge. Therefore, parameters that support clinical decision making are sought. Blood-based biomarkers have the potential to provide valuable information in addition to the established prognostic factors. Neuronal biomarkers of acute or degenerative neuronal injury have shown to be reliably detected in plasma. These biomarkers are well-established in neurodegenerative pathology, such as Alzheimer's disease. In this study, we explored the association between stroke diameter and plasma biomarkers for neuronal injury and tau pathophysiology (brain-derived tau [BD-tau], phosphorylated-tau-217 [p-tau21] and neurofilament light [NfL]) in patients (n = 193) admitted to the acute ward, Akershus University Hospital. All patients received a final diagnosis of AIS, transient ischemic attack or stroke mimics. Blood samples were obtained the day after admission. We find that levels of BD-tau (p = .004) and NfL (p = .011) were higher after AIS than in patients with stroke mimics. The cortical stroke diameter correlated with BD-tau (tau-b = 0.64, p < .001) and p-tau217 (tau-b = 0.36, p = .003). Linear regression confirmed BD-tau to be the strongest variable associated with stroke diameter, pointing to the potential clinical value of plasma BD-tau in outcome prediction after AIS.
| S-EPMC11563507 | biostudies-literature
Project description:As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and (11)C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.
| S-EPMC3887360 | biostudies-other
Project description:Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability, which gravely burdens the global economy. Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy. Even so, patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury. It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies. Regarding the pathogenesis, multiple pathological events trigger the activation of cell death pathways. Particular attention should be devoted to excitotoxicity, oxidative stress, and inflammatory responses. Thus, in this article, we first review the principal mechanisms underlying neuronal death mediated by these significant events, such as intrinsic and extrinsic apoptosis, ferroptosis, parthanatos, pyroptosis, necroptosis, and autophagic cell death. Then, we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.
| S-EPMC9554175 | biostudies-literature
Project description:Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activated. We have previously demonstrated that the UPR pathway initiated by ATF6 is pro-survival in transient ischemic stroke. However, the effect of ATF6 activation on the outcome after permanent ischemic stroke remains unknown. Here, we addressed this knowledge gap. Method: sATF6-KI mice with functional short-form ATF6 (sATF6) predominantly expressed in forebrain neurons were subjected to two ischemic stroke models: photothrombotic stroke and permanent middle cerebral artery occlusion (pMCAO). Both short-term and long-term functional outcomes were evaluated. Changes in neuroinflammation and cerebrovascular density after pMCAO were also assessed. Results: Compared to littermate controls, sATF6-KI mice performed significantly better in open field, cylinder, and foot fault tests on day 1 or 3 after photothrombotic stroke. However, on days 7 and 14 after stroke, the performance of these functional tests was not significantly different between groups, which is likely related to mild brain damage associated with this stroke model. Thus, to evaluate the long-term effects of ATF6 activation in permanent stroke, we turned to our pMCAO model. We first found that on day 4 after pMCAO, functional outcome was better, and infarct volumes were smaller in sATF6-KI mice vs controls. Next, the 15-day stroke outcome study indicated that compared to control mice, sATF6-KI mice consistently exhibited improved performance in neurologic scoring, tight rope test, and tape removal test, after pMCAO. Moreover, sATF6-KI mice showed higher vascular density and lower activation of both astrocytes and microglia around stroke regions on day 16 after pMCAO. Conclusions: Here, we presented the first evidence that activation of the ATF6 UPR branch is protective in permanent ischemic stroke, which further supports the therapeutic potential of targeting the ATF6 pathway in stroke.
| S-EPMC9614111 | biostudies-literature
Project description:AimHyperlipidemia is a common comorbidity of stroke patients, elucidating the mechanism that underlies the exacerbated ischemic brain injury after stroke with hyperlipidemia is emerging as a significant clinical problem due to the growing proportion of hyperlipidemic stroke patients.MethodsMice were fed a high-fat diet for 12 weeks to induce hyperlipidemia. Transient middle cerebral artery occlusion was induced as a mouse model of ischemic stroke. Emx1Cre mice were crossed with Mef2cfl/fl mice to specifically deplete Mef2c in neurons.ResultsWe reported that hyperlipidemia significantly aggravated neuronal necroptosis and exacerbated long-term neurological deficits following ischemic stroke in mice. Mechanistically, Cflar, an upstream necroptotic regulator, was alternatively spliced into pro-necroptotic isoform (CflarR) in ischemic neurons of hyperlipidemic mice. Neuronal Mef2c was a transcription factor modulating Cflar splicing and upregulated by hyperlipidemia following stroke. Neuronal specific Mef2c depletion reduced cerebral level of CflarR and cFLIPR (translated by CflarR), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice.ConclusionsOur study highlights the pathogenic role of CflarR splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes CflarR splicing as a potential therapeutic target for hyperlipidemic stroke patients.
| S-EPMC11625962 | biostudies-literature
Project description:Acute ischemic stroke (AIS) is a severe disorder characterized by complex pathophysiological processes, which can lead to disability and death. This study aimed to determine necroptosis-associated genes in acute ischemic stroke (AIS) and to investigate their potential as diagnostic and therapeutic targets for AIS. Expression profiling data were acquired from the Gene Expression Omnibus database, and necroptosis-associated genes were retrieved from GeneCards. The differentially expressed genes (DEGs) and necroptosis-related genes were intersected to obtain the necroptosis-related DEGs (NRDEGs) in AIS. In AIS, a total of 76 genes associated with necroptosis (referred to as NRDEGs) were identified. Enrichment analysis of these genes revealed that they were primarily enriched in pathways known to induce necroptosis. Using weighted gene co-expression network analysis (WGCNA), five co-expression modules consisting of NRDEGs were identified, along with two modules that exhibited a strong correlation with AIS. Protein-protein interaction (PPI) analysis resulted in the identification of 20 hub genes. The Least absolute shrinkage and selection operator (LASSO) regression model demonstrated promising potential for diagnostic prediction. The receiver operating characteristic (ROC) curve validated the diagnostic model and selected nine characteristic genes that exhibited statistically significant differences (p < 0.05). By employing consensus clustering, distinct patterns of necroptosis were identified using these nine signature genes. The results were validated by quantitative PCR (qPCR) in venous blood from patients with AIS and healthy controls and HT22 cells, as well as external datasets. Furthermore, the analyzed ceRNA network included nine lncRNAs, six miRNAs, and three mRNAs. Overall, this study offers novel insights into the molecular mechanisms underlying NRDEGs in AIS. The findings provide valuable evidence and contribute to our understanding of the disease.
| S-EPMC11693621 | biostudies-literature
Project description:Programmed cell death contributes to neurological damage in ischemic stroke, especially during the reperfusion stage. Several cell death pathways have been tested preclinically and clinically, including ferroptosis, necroptosis, and apoptosis. However, the sequence and complex interplay between cell death pathways during ischemia/reperfusion remains under investigation. Here, we unbiasedly investigated cell death pathways during ischemia/reperfusion by utilizing RNA sequencing analysis and immunoblot assays and revealed that ferroptosis and necroptosis occurred early post-reperfusion, followed by apoptosis. Ferroptosis inhibitor Liproxstatin-1 effectively inhibited necroptosis during reperfusion, while the necroptosis inhibitor Necrostatin-1 suppressed protein expression consistent with ferroptosis activation. Protein-protein interaction analysis and iron chelation therapy by deferoxamine mesylate indicate that iron is capable of promoting both ferroptosis and necroptosis in middle cerebral artery occlusion/repression modeled mice. Treatment of cells with iron led to a disruption in redox balance with activated necroptosis and increased susceptibility to ferroptosis. Collectively, these data uncovered a complex interplay between ferroptosis and necroptosis during ischemic stroke and indicated that multiple programmed cell death pathways may be targeted co-currently.
| S-EPMC11402992 | biostudies-literature
Project description:Endothelium (EC) is a key component of blood-brain barrier (BBB), and has an important position in the neurovascular unit. Its dysfunction and death after cerebral ischemic/reperfusion (I/R) injury not only promote evolution of neuroinflammation and brain edema, but also increase the risk of intracerebral hemorrhage of thrombolytic therapies. However, the mechanism and specific interventions of EC death after I/R injury are poorly understood. Here we showed that necroptosis was a mechanism underlying EC death, which promoted BBB breakdown after I/R injury. Treatment of rats with receptor interacting protein kinase 1 (RIPK1)-inhibitor, necrostatin-1 reduced endothelial necroptosis and BBB leakage. We furthermore showed that perivascular M1-like microglia-induced endothelial necroptosis leading to BBB disruption requires tumor necrosis factor-α (TNF-α) secreted by M1 type microglia and its receptor, TNF receptor 1 (TNFR1), on endothelium as the primary mediators of these effects. More importantly, anti-TNFα (infliximab, a potent clinically used drug) treatment significantly ameliorate endothelial necroptosis, BBB destruction and improve stroke outcomes. Our data identify a previously unexplored role for endothelial necroptosis in BBB disruption and suggest infliximab might serve as a potential drug for stroke therapy.
| S-EPMC6586814 | biostudies-literature