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Cells
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Signaling and Mechanisms of Cell Death in the Nervous System
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Signaling and Mechanisms of Cell Death in the Nervous System

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 March 2022) | Viewed by 18169

Special Issue Editors

Dr. Wanli Smith

E-Mail Website
Guest Editor
Johns Hopkins University, School of Medicine, Baltimore, MA, USA
Interests: Parkinson’s Disease; Obesity; Alzheimer’s disease; Neuronal cell death and protein aggregation in neuropsychiatric conditions
Dr. Yulan Xiong

E-Mail Website
Co-Guest Editor
Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
Interests: molecular mechanisms underlying neurodegenerative diseases; Parkinson’s disease (PD); identifying molecular therapeutic targets that leads to developing effective biomarkers and treatments for Parkinson’s disease (PD)

Special Issue Information

Dear Colleagues,

Cell death in CNS is the key pathological hallmark for various neuropsychiatric disorders. Cell death in neurons results in various CNS dysfunction, neuronal injury and degeneration. Cell death in microglia and astrocytes results in neuroinflammation and secondary neurodegeneration. Understanding the signaling pathways and mechanisms underlying CNS cell death will provide the valuable drug targets and facilitate the development of therapeutics for prevention and treatment.

Cell death in CNS can be apoptosis, necrosis, parthanatos, pyroptosis, necroptosis and other undefined types of death. CNS cell death occurred by various internal and external pathological insults. The external insults include physical and social stress, chemical toxicants and various pathogens. The internal insults include injury, ischemia, inflammation, oxidative stress, etc. Diverse mechanisms of CNS cell death under various pathophysiological conditions have been suggested, including oxidative stress, mitochondria dysfunction, ER stress, impairment of ubiquitin/proteasome, and lysosome/autophagy related protein degradation pathways, increase in intracellular calcium, over-activation of glutamate receptors, and activation of microglia and astrocytes, dysfunction of cell-cell interaction, disruption of the blood-brain barrier (BBB) integrity, and other unidentified novel cell death pathways. Various neuronal protection strategies have been investigated over decades. Thus far, disease-modifying drugs targeting CNS cell death are still under developed. More research efforts are needed to develop novel effective strategies against CNS cell death and its related disorders.

This Special Issue aims to promote the research on the understanding of the pathological roles and molecular mechanisms underlying CNS cell death and its related neuropsychiatric disorders, and the research on novel biomarkers, drug targets and neuroprotective strategies. As the editor for this issue, I call on all researchers in this dynamic field to contribute articles and help to make this issue a successful contribution to neuroscience.

Dr. Wanli Smith
Guest Editors
Dr. Yulan Xiong
Co-Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuronal death
  • necrosis
  • apoptosis
  • parthanatos
  • inflammation
  • oxidative stress
  • cell signaling
  • neuroprotection
  • lysosome/autophagy
  • ubiquitin/proteasome

Published Papers (6 papers)

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Research

17 pages, 36813 KiB  
Article
Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke
by Peiying Deng, Liang Wang, Qiongqiong Zhang, Suhui Chen, Yamin Zhang, Hong Xu, Hui Chen, Yi Xu, Wei He, Jianmin Zhang and Hua Sun
Cells 2022, 11(5), 820; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050820 - 26 Feb 2022
Cited by 17 | Viewed by 3634
Abstract
This paper aimed to explore the roles of the combination of electroacupuncture (EA) and induced pluripotent stem cell-derived small extracellular vesicles (iPSC-EVs) on mice with ischemic stroke and the underlying mechanisms. A focal cerebral ischemia model was established in C57BL/6 mice through middle [...] Read more.
This paper aimed to explore the roles of the combination of electroacupuncture (EA) and induced pluripotent stem cell-derived small extracellular vesicles (iPSC-EVs) on mice with ischemic stroke and the underlying mechanisms. A focal cerebral ischemia model was established in C57BL/6 mice through middle cerebral artery occlusion (MCAO). After 3 days, neurological impairment and motor function were examined by performing behavioral tests. The infarct volume and neuronal apoptosis were examined using TTC staining and TUNEL assays. Flow cytometry was performed to assess the proliferation of T lymphocytes. The changes in the interleukin (IL)-33/ST2 axis were evaluated by immunofluorescence and Western blotting. The combination of EA and iPSC-EVs treatment ameliorated neurological impairments and reduced the infarct volume and neuronal apoptosis in MCAO mice. EA plus iPSC-EVs suppressed T helper (Th1) and Th17 responses and promoted the regulatory T cell (Treg) response. In addition, EA plus iPSC-EVs exerted neuroprotective effects by regulating the IL-33/ST2 axis and inhibiting the microglia and astrocyte activation. Taken together, the study shows that EA and iPSC-EVs exerted a synergistic neuroprotective effect in MCAO mice, and this treatment may represent a novel potent therapy for ischemic stroke and damage to other tissues. Full article
(This article belongs to the Special Issue Signaling and Mechanisms of Cell Death in the Nervous System)
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14 pages, 2740 KiB  
Article
Global Reprogramming of Apoptosis-Related Genes during Brain Development
by Wei Jiang, Liang Chen and Sika Zheng
Cells 2021, 10(11), 2901; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112901 - 27 Oct 2021
Cited by 10 | Viewed by 2764
Abstract
To enable long-term survival, mammalian adult neurons exhibit unique apoptosis competence. Questions remain as to whether and how neurons globally reprogram the expression of apoptotic genes during development. We systematically examined the in vivo expression of 1923 apoptosis-related genes and associated histone modifications [...] Read more.
To enable long-term survival, mammalian adult neurons exhibit unique apoptosis competence. Questions remain as to whether and how neurons globally reprogram the expression of apoptotic genes during development. We systematically examined the in vivo expression of 1923 apoptosis-related genes and associated histone modifications at eight developmental ages of mouse brains. Most apoptotic genes displayed consistent temporal patterns across the forebrain, midbrain, and hindbrain, suggesting ubiquitous robust developmental reprogramming. Although both anti- and pro-apoptotic genes can be up- or downregulated, half the regulatory events in the classical apoptosis pathway are downregulation of pro-apoptotic genes. Reduced expression in initiator caspases, apoptosome, and pro-apoptotic Bcl-2 family members restrains effector caspase activation and attenuates neuronal apoptosis. The developmental downregulation of apoptotic genes is attributed to decreasing histone-3-lysine-4-trimethylation (H3K4me3) signals at promoters, where histone-3-lysine-27-trimethylation (H3K27me3) rarely changes. By contrast, repressive H3K27me3 marks are lost in the upregulated gene groups, for which developmental H3K4me3 changes are not predictive. Hence, developing brains remove epigenetic H3K4me3 and H3K27me3 marks on different apoptotic gene groups, contributing to their downregulation and upregulation, respectively. As such, neurons drastically alter global apoptotic gene expression during development to transform apoptosis controls. Research into neuronal cell death should consider maturation stages as a biological variable. Full article
(This article belongs to the Special Issue Signaling and Mechanisms of Cell Death in the Nervous System)
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20 pages, 4021 KiB  
Article
The Proapoptotic Gene Bad Regulates Brain Development via p53-Mediated Stress Signals in Zebrafish
by Jo-Chi Hung, Jen-Leih Wu, Huei-Ching Li, Hsuan-Wen Chiu and Jiann-Ruey Hong
Cells 2021, 10(11), 2820; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112820 - 20 Oct 2021
Cited by 3 | Viewed by 2188
Abstract
Studies have shown that the BH3-only domain Bad regulates brain development via the control of programmed cell death (PCD), but very few studies have addressed its effect on the molecular signaling of brain development in the system. In this work, we examined the [...] Read more.
Studies have shown that the BH3-only domain Bad regulates brain development via the control of programmed cell death (PCD), but very few studies have addressed its effect on the molecular signaling of brain development in the system. In this work, we examined the novel role of zebrafish Bad in initial programmed cell death for brain morphogenesis through the priming of p53-mediated stress signaling. In a biological function study on the knockdown of Bad by morpholino oligonucleotides, at 24 h post-fertilization (hpf) Bad defects induced abnormal hindbrain development, as determined in a tissue section by means of HE staining which traced the damaged hindbrain. Then, genome-wide approaches for monitoring either the upregulation of apoptotic-related genes (11.8%) or the downregulation of brain development-related genes (29%) at the 24 hpf stage were implemented. The p53/caspase-8-mediated apoptotic death pathway was strongly involved, with the pathway being strongly reversed in a p53 mutant (p53M214K) line during Bad knockdown. Furthermore, we propose the involvement of a p53-mediated stress signal which is correlated with regulating Bad loss-mediated brain defects. We found that some major genes in brain development, such as crybb1, pva1b5, irx4a, pax7a, and fabp7a, were dramatically restored in the p53M214K line, and brain development recovered to return movement behavior to normal. Our findings suggest that Bad is required for (PCD) control, exerting a p53 stress signal on caspase-8/tBid-mediated death signaling and brain development-related gene regulation. Full article
(This article belongs to the Special Issue Signaling and Mechanisms of Cell Death in the Nervous System)
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16 pages, 3805 KiB  
Article
Exendin-4 Pretreatment Attenuates Kainic Acid-Induced Hippocampal Neuronal Death
by Yu-Jeong Ahn, Hyun-Joo Shin, Eun-Ae Jeong, Hyeong-Seok An, Jong-Youl Lee, Hye-Min Jang, Kyung-Eun Kim, Jaewoong Lee, Meong-Cheol Shin and Gu-Seob Roh
Cells 2021, 10(10), 2527; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102527 - 24 Sep 2021
Cited by 6 | Viewed by 2609
Abstract
Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in [...] Read more.
Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood–brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways. Full article
(This article belongs to the Special Issue Signaling and Mechanisms of Cell Death in the Nervous System)
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16 pages, 5134 KiB  
Article
Activation of Nrf2 in Astrocytes Suppressed PD-Like Phenotypes via Antioxidant and Autophagy Pathways in Rat and Drosophila Models
by Qing Guo, Bing Wang, Xiaobo Wang, Wanli W. Smith, Yi Zhu and Zhaohui Liu
Cells 2021, 10(8), 1850; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081850 - 21 Jul 2021
Cited by 13 | Viewed by 3166
Abstract
The oxidative-stress-induced impairment of autophagy plays a critical role in the pathogenesis of Parkinson’s disease (PD). In this study, we investigated whether the alteration of Nrf2 in astrocytes protected against 6-OHDA (6-hydroxydopamine)- and rotenone-induced PD-like phenotypes, using 6-OHDA-induced rat PD and rotenone-induced Drosophila [...] Read more.
The oxidative-stress-induced impairment of autophagy plays a critical role in the pathogenesis of Parkinson’s disease (PD). In this study, we investigated whether the alteration of Nrf2 in astrocytes protected against 6-OHDA (6-hydroxydopamine)- and rotenone-induced PD-like phenotypes, using 6-OHDA-induced rat PD and rotenone-induced Drosophila PD models. In the PD rat model, we found that Nrf2 expression was significantly higher in astrocytes than in neurons. CDDO-Me (CDDO methyl ester, an Nrf2 inducer) administration attenuated PD-like neurodegeneration mainly through Nrf2 activation in astrocytes by activating the antioxidant signaling pathway and enhancing autophagy in the substantia nigra and striatum. In the PD Drosophila model, the overexpression of Nrf2 in glial cells displayed more protective effects than such overexpression in neurons. Increased Nrf2 expression in glial cells significantly reduced oxidative stress and enhanced autophagy in the brain tissue. The administration of the Nrf2 inhibitor ML385 reduced the neuroprotective effect of Nrf2 through the inhibition of the antioxidant signaling pathway and autophagy pathway. The autophagy inhibitor 3-MA partially reduced the neuroprotective effect of Nrf2 through the inhibition of the autophagy pathway, but not the antioxidant signaling pathway. Moreover, Nrf2 knockdown caused neurodegeneration in flies. Treatment with CDDO-Me attenuated the Nrf2-knockdown-induced degeneration in the flies through the activation of the antioxidant signaling pathway and increased autophagy. An autophagy inducer, rapamycin, partially rescued the neurodegeneration in Nrf2-knockdown Drosophila by enhancing autophagy. Our results indicate that the activation of the Nrf2-linked signaling pathways in glial cells plays an important neuroprotective role in PD models. Our findings not only provide a novel insight into the mechanisms of Nrf2–antioxidant–autophagy signaling, but also provide potential targets for PD interventions. Full article
(This article belongs to the Special Issue Signaling and Mechanisms of Cell Death in the Nervous System)
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16 pages, 3293 KiB  
Article
Zika Virus Induces Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)-Mediated Apoptosis in Human Neural Progenitor Cells
by Jae Kyung Lee, Ji-Ae Kim, Soo-Jin Oh, Eun-Woo Lee and Ok Sarah Shin
Cells 2020, 9(11), 2487; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112487 - 16 Nov 2020
Cited by 13 | Viewed by 2790
Abstract
Zika virus (ZIKV) remains as a public health threat due to the congenital birth defects the virus causes following infection of pregnant women. Congenital microcephaly is among the neurodevelopmental disorders the virus can cause in newborns, and this defect has been associated with [...] Read more.
Zika virus (ZIKV) remains as a public health threat due to the congenital birth defects the virus causes following infection of pregnant women. Congenital microcephaly is among the neurodevelopmental disorders the virus can cause in newborns, and this defect has been associated with ZIKV-mediated cytopathic effects in human neural progenitor cells (hNPCs). In this study, we investigated the cellular changes that occur in hNPCs in response to ZIKV (African and Asian lineages)-induced cytopathic effects. Transmission electron microscopy showed the progress of cell death as well as the formation of numerous vacuoles in the cytoplasm of ZIKV-infected hNPCs. Infection with both African and Asian lineages of ZIKV induced apoptosis, as demonstrated by the increased activation of caspase 3/7, 8, and 9. Increased levels of proinflammatory cytokines and chemokines (IL-6, IL-8, IL-1β) were also detected in ZIKV-infected hNPCs, while z-VAD-fmk-induced inhibition of cell death suppressed ZIKV-mediated cytokine production in a dose-dependent manner. ZIKV-infected hNPCs also displayed significantly elevated gene expression levels of the pro-apoptotic Bcl2-mediated family, in particular, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, TRAIL signaling led to augmented ZIKV-mediated cell death and the knockdown of TRAIL-mediated signaling adaptor, FADD, resulted in enhanced ZIKV replication. In conclusion, our findings provide cellular insights into the cytopathic effects induced by ZIKV infection of hNPCs. Full article
(This article belongs to the Special Issue Signaling and Mechanisms of Cell Death in the Nervous System)
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