Nonapoptotic caspases in neural development and in anesthesia-induced neurotoxicity

Sarić, Nemanja; Hashimoto-Torii, Kazue; Jevtović-Todorović, Vesna; Ishibashi, Nobuyuki

doi:10.1016/j.tins.2022.03.007

Cited by 12 publications

(6 citation statements)

References 119 publications

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“…Because caspase-3 activation can occur without neuronal death ( Acarin et al, 2007 ; Erturk et al, 2014 ; Khatri et al, 2018 ; Saric et al, 2022 ), we examined whether the number of viable neurons were changed with Cul3 deletion. First, we confirmed that DAPI-stained cells were decreased in Cul3 deletion cultures ( Figures 3E , F ), and that this decrease was reversed by caspase-3 inhibition ( Figures 3E , F ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies revealed that caspase-3 activity regulates not only cell death, but also cell morphology ( Kaplan et al, 2010 ; Erturk et al, 2014 ; Guo et al, 2016 ; Hollville and Deshmukh, 2018 ; Amar et al, 2021 ; Morandell et al, 2021 ). Thus, we hypothesized that some of our neuronal morphology changes may result from elevated caspase-3 activity as well ( Saric et al, 2022 ). To test this, we inhibited caspase-3 and examined neuronal morphology.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies revealed that Cul3 loss leads to a significant increase of caspase-3 activation ( Kaplan et al, 2010 ; Amar et al, 2021 ; Morandell et al, 2021 ) and caspase-3 activation level is a key regulatory mechanism of cell morphology and programmed cell death ( Erturk et al, 2014 ; Hollville and Deshmukh, 2018 ; Saric et al, 2022 ). By inhibiting caspase-3 activity, we discovered that the alteration in both dendrites and spines can be largely reversed to WT control levels.…”

Section: Discussionmentioning

confidence: 99%

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Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons

Xia,

Singh,

Wang

et al. 2024

Front. Cell. Neurosci.

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Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders (NDDs) in which children display differences in social interaction/communication and repetitive stereotyped behaviors along with variable associated features. Cul3, a gene linked to ASD, encodes CUL3 (CULLIN-3), a protein that serves as a key component of a ubiquitin ligase complex with unclear function in neurons. Cul3 homozygous deletion in mice is embryonic lethal; thus, we examine the role of Cul3 deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures. Homozygous deletion of Cul3 significantly decreased dendritic complexity and dendritic length, as well as axon formation. Synaptic spine density significantly increased, mainly in thin and stubby spines along with decreased average spine volume in Cul3 knockouts. Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged. Based on previous studies implicating elevated caspase-3 after Cul3 deletion, we demonstrated increased caspase-3 in our neuronal cultures and decreased neuronal cell viability. We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition. Studies have also implicated caspase-3 in neuronal morphological changes. We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes. Overall, these data provide additional evidence that Cul3 regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons

Xia,

Singh,

Wang

et al. 2024

Front. Cell. Neurosci.

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“…The expression changes of pro-apoptotic genes, including casp3a and casp3b , at 12 to 72 hpf were consistent with the results of TUNEL staining, which demonstrated the effect of propofol on apoptosis during zebrafish development from the molecular perspective. More importantly, caspase activation is increasingly associated with physiological and anesthesia-induced pathological non-apoptotic outcomes that do not lead to neuronal death, but have major effects on cell morphology and function [ 62 ]. The expression of the caspase family at the transcriptional level increased with the development of zebrafish embryos; however, TUNEL staining showed that the number of apoptotic cells was highest at 24 hpf.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic mechanism of propofol-induced developmental toxicity in zebrafish embryos

Yuan

Jia

et al. 2023

PLoS ONE

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General anesthetics can cause neurological damage and long-term behavioral/cognitive impairment during fetal and early postnatal life. However, the adverse influence on embryo development induced by propofol is unclear. We used embryonic zebrafish to explore the effects of propofol on embryonic and larval growth and development, and the related apoptotic mechanism. Zebrafish embryos were immersed in propofol (1, 2, 3, 4, and 5 μg/ml) dissolved in E3 medium from 6 to 48 hours post fertilization (hpf). The survival rate, locomotion, heart rate, hatchability, deformity rate, and body length were analyzed at defined stages. Terminal deoxynucleotidyl transferase nick-end-labeling was used to detect zebrafish embryo apoptosis, and the expression levels of apoptosis-related genes were determined using quantitative real-time reverse transcription PCR and whole-mount in situ hybridization. Larvae at 48 hpf were anesthetized by immersion in E3 culture medium containing 2 μg/ml propofol, the reasonable anesthetic concentration for zebrafish embryos, which caused significant caudal fin dysplasia, light pigmentation, edema, hemorrhage, and spinal deformity, and decreased the hatchability, body length, and heart rate. The numbers of apoptotic cells in propofol-treated 12, 48 and 72 hpf embryos increased significantly, and the mRNA expression levels of intrinsic apoptosis pathway-related casp3a, casp3b, casp9, and baxb genes were upregulated, mainly in the head and tail. Propofol decreased apoptosis in the head and back of 24 hpf zebrafish, which was consistent with the mRNA expression analysis. Our findings demonstrated that zebrafish embryos and larvae exposed to propofol experienced developmental toxicity, which correlated with the intrinsic apoptosis pathway with casp3a, casp3b, casp9, and baxb as the key genes.

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“…A large-scale study suggested an association between increased risk of LHON triggering and alcohol only in patients with a heavy alcohol intake [ 16 ]. Alcohol neuropathogenicity has been known for many years [ 70 ], and the association of either acute or chronic ethanol exposure with caspase 3 activation, neuronal cell death, and neurodegeneration has been demonstrated in rodent models [ 71 ]. Mitochondria are the primary targets of chronic alcohol intake due to direct or indirect inhibition of complexes I and III and increased production of ROS and reactive nitrogen species (RNS) resulting from ethanol metabolism [ 72 ].…”

Section: Environmental Risk Factorsmentioning

confidence: 99%

The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber’s Hereditary Optic Neuropathy

Layrolle,

Orssaud,

Leleu

et al. 2024

Biomedicines

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Optic neuropathies are characterized by the degeneration of the optic nerves and represent a considerable individual and societal burden. Notably, Leber’s hereditary optic neuropathy (LHON) is a devastating vision disease caused by mitochondrial gene mutations that hinder oxidative phosphorylation and increase oxidative stress, leading to the loss of retinal ganglion neurons and axons. Loss of vision is rapid and severe, predominantly in young adults. Penetrance is incomplete, and the time of onset is unpredictable. Recent findings revealed that the incidence of genetic LHON susceptibility is around 1 in 1000, much higher than believed till now. Environmental factors are critical in LHON triggering or severity. Families at risk have a very strong demand for how to prevent the onset or limit the severity of the disease. Here, we review recent knowledge of the extrinsic determinants of LHON expression, including lifestyle, dietary supplements, common chemicals, and drugs.

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Nonapoptotic caspases in neural development and in anesthesia-induced neurotoxicity

Cited by 12 publications

References 119 publications

Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons

Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons

Apoptotic mechanism of propofol-induced developmental toxicity in zebrafish embryos

The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber’s Hereditary Optic Neuropathy

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