Non-Canonical Roles of Apoptotic Caspases in the Nervous System

Dehkordi, Mahshid H.; Munn, Robert G.K.; Fearnhead, Howard O.

doi:10.3389/fcell.2022.840023

Cited by 33 publications

(16 citation statements)

References 134 publications

(156 reference statements)

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“…Surprisingly, we observed an important expression of CC3 in normoxic conditions. This might be explained by apoptosis in the cell culture or by physiological functions of CC3 as recently described [ 18 , 19 ].…”

Section: Resultsmentioning

confidence: 91%

Re-Evaluating the Relevance of the Oxygen–Glucose Deprivation Model in Ischemic Stroke: The Example of Cdk Inhibition

D'aes

Marlier

Verteneuil

et al. 2023

IJMS

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Previous research has shown that cyclin-dependent kinases (Cdks) that play physiological roles in cell cycle regulation become activated in post-mitotic neurons after ischemic stroke, resulting in apoptotic neuronal death. In this article, we report our results using the widely used oxygen–glucose deprivation (OGD) in vitro model of ischemic stroke on primary mouse cortical neurons to investigate whether Cdk7, as part of the Cdk-activating kinase (CAK) complex that activates cell cycle Cdks, might be a regulator of ischemic neuronal death and may potentially constitute a therapeutic target for neuroprotection. We found no evidence of neuroprotection with either pharmacological or genetic invalidation of Cdk7. Despite the well-established idea that apoptosis contributes to cell death in the ischemic penumbra, we also found no evidence of apoptosis in the OGD model. This could explain the absence of neuroprotection following Cdk7 invalidation in this model. Neurons exposed to OGD seem predisposed to die in an NMDA receptor-dependent manner that could not be prevented further downstream. Given the direct exposure of neurons to anoxia or severe hypoxia, it is questionable how relevant OGD is for modeling the ischemic penumbra. Due to remaining uncertainties about cell death after OGD, caution is warranted when using this in vitro model to identify new stroke therapies.

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Section: Resultsmentioning

confidence: 91%

Re-Evaluating the Relevance of the Oxygen–Glucose Deprivation Model in Ischemic Stroke: The Example of Cdk Inhibition

D'aes

Marlier

Verteneuil

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Human Caspase 1 and mouse Caspase 11 (synonym Casp4) have been linked [ 28 ] and therefore considered inflammatory caspases. Other non-canonical roles are emerging for many caspases including apoptosis and synaptic plasticity [ 29 , 30 ], and the dynamic of caspase molecules may be diverse. To briefly clarify, rat Casp4 , based on the HGNC Comparison of Orthology Prediction ( https://www.genenames.org ), CASP4 and CASP5 are the human orthologs, and Casp11 (synonym Casp4 ) is the mouse ortholog.…”

Section: Resultsmentioning

confidence: 99%

The Identification of Human Translational Biomarkers of Neuropathic Pain and Cross-Species Validation Using an Animal Model

et al. 2022

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Neuropathic pain is a common chronic condition, which remains poorly understood. Many patients receiving treatment continue to experience severe pain, due to limited diagnostic/treatment management programmes. The development of objective clinical diagnostic/treatment strategies requires identification of robust biomarkers of neuropathic pain. To this end, we looked to identify biomarkers of chronic neuropathic pain by assessing gene expression profiles in an animal model of neuropathic pain, and differential gene expression in patients to determine the potential translatability. We demonstrated cross-species validation of several genes including those identified through bioinformatic analysis by assessing their expression in blood samples from neuropathic pain patients, according to conservative assessments of significance measured using Bonferroni-corrected p-values. These include CASP5 (p = 0.00226), CASP8 (p = 0.00587), CASP9 (p = 2.09 × 10−9), FPR2 (p = 0.00278), SH3BGRL3 (p = 0.00633), and TMEM88 (p = 0.00038). A ROC analysis revealed several combinations of genes to show high levels of discriminatory power in the comparison of neuropathic pain patients and control participants, of which the combination SH3BGRL3, TMEM88, and CASP9 achieved the highest level (AUROC = 0.923). The CASP9 gene was found to be common in five combinations of three genes revealing the highest levels of discriminatory power. In contrast, the gene combination PLAC8, ROMO1, and A3GALT2 showed the highest levels of discriminatory power in the comparison of neuropathic pain and nociceptive pain (AUROC = 0.919), when patients were grouped by S-LANSS scores. Molecules that demonstrate an active role in neuropathic pain have the potential to be developed into a biological measure for objective diagnostic tests, or as novel drug targets for improved pain management.

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“…However, these caspases can also play underappreciated non-canonical roles. For example, apoptotic caspases can also have roles in a range of neuronal cell behaviours and even in antiapoptotic mechanisms ( 43 , 44 ). Moreover, caspase 8, which is essential for death receptor-induced apoptosis, has also been shown to have a role in the homeostatic control in the adult immune system ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells induce HIV-1 latency reversal after treatment with pan-caspase inhibitors

et al. 2022

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The establishment of a latency reservoir is the major obstacle for a cure of HIV-1. The shock-and-kill strategy aims to reactivate HIV-1 replication in HIV -1 latently infected cells, exposing the HIV-1-infected cells to cytotoxic lymphocytes. However, none of the latency reversal agents (LRAs) tested so far have shown the desired effect in people living with HIV-1. We observed that NK cells stimulated with a pan-caspase inhibitor induced latency reversal in co-cultures with HIV-1 latently infected cells. Synergy in HIV-1 reactivation was observed with LRAs prostratin and JQ1. The supernatants of the pan-caspase inhibitor-treated NK cells activated the HIV-1 LTR promoter, indicating that a secreted factor by NK cells was responsible for the HIV-1 reactivation. Assessing changes in the secreted cytokine profile of pan-caspase inhibitor-treated NK cells revealed increased levels of the HIV-1 suppressor chemokines MIP1α (CCL3), MIP1β (CCL4) and RANTES (CCL5). However, these cytokines individually or together did not induce LTR promoter activation, suggesting that CCL3-5 were not responsible for the observed HIV-1 reactivation. The cytokine profile did indicate that pan-caspase inhibitors induce NK cell activation. Altogether, our approach might be–in combination with other shock-and-kill strategies or LRAs–a strategy for reducing viral latency reservoirs and a step forward towards eradication of functionally active HIV-1 in infected individuals.

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Non-Canonical Roles of Apoptotic Caspases in the Nervous System

Cited by 33 publications

References 134 publications

Re-Evaluating the Relevance of the Oxygen–Glucose Deprivation Model in Ischemic Stroke: The Example of Cdk Inhibition

Re-Evaluating the Relevance of the Oxygen–Glucose Deprivation Model in Ischemic Stroke: The Example of Cdk Inhibition

The Identification of Human Translational Biomarkers of Neuropathic Pain and Cross-Species Validation Using an Animal Model

Natural killer cells induce HIV-1 latency reversal after treatment with pan-caspase inhibitors

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