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Special Issue "Neuron Cell Death"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular and Cellular Biology".

Deadline for manuscript submissions: closed (15 September 2018)

Special Issue Editors

Guest Editor
Prof. Dr. Adalberto Merighi

Universita degli Studi di Torino, Department of Veterinary Clinical Sciences, Torino, Italy
Website | E-Mail
Guest Editor
Prof. Dr. Laura Lossi

Universita degli Studi di Torino, Department of Veterinary Clinical Sciences, Torino, Italy
Website | E-Mail

Special Issue Information

Dear Colleagues,

The discovery of neuronal cell death dates back to the 19th century. Nowadays, the notion that cell death is a phenomenon occurring during the entire life course of the nervous system, from neurogenesis to adulthood and old age, is fully established. Moreover, it is widely accepted that death of neurons occurs in certain pathologies of the brain, including neurodegenerative diseases. The dichotomy between apoptosis, as the prototype of programmed cell death (PCD), and necrosis, as the prototype of death caused by an external insult, must be carefully reconsidered, as different types of PCD including apoptosis, autophagy, pyroptosis, and oncosis have all been demonstrated in neurons. These modes of PCD may be triggered by different stimuli, but share some intracellular pathways such that different types of cell death may affect the same population of neurons according to several intrinsic and extrinsic factors, so that a mixed morphology is often observed also depending on degrees of differentiation, activity and injury.

This Special Issue focuses on the recent progress in understanding the cellular and molecular biology of the death of central neurons, as well as the underlying mechanisms of PCD in the normal and pathological brain. Molecular alterations of these mechanisms represent promising diagnostic and prognostic molecular markers and therapeutic targets for neurodegenerative diseases and age-related cognitive impairment. The discovery of specific biomarkers, as well as the specific changes in gene expression patterns and alterations of the normal protein profile of the nerve cell in cell culture and animal will also be considered in this Special Issue.

Prof. Dr. Adalberto Merighi
Prof. Dr. Laura Lossi
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access monthly 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 1800 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

  • Neurons
  • Cell death
  • Apoptosis
  • Oncosis
  • Pyroptosis
  • Autophagy
  • Neurogenesis
  • Aging
  • Neurodegeneration
  • Programmed cell death
  • Necrosis

Published Papers (8 papers)

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Research

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Open AccessArticle Chaperone-E3 Ligase Complex HSP70-CHIP Mediates Ubiquitination of Ribosomal Protein S3
Int. J. Mol. Sci. 2018, 19(9), 2723; https://doi.org/10.3390/ijms19092723
Received: 3 July 2018 / Revised: 7 September 2018 / Accepted: 10 September 2018 / Published: 12 September 2018
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Abstract
In addition to its role in ribosome biogenesis, ribosomal protein S3 (RPS3), a component of the 40S ribosomal subunit, has been suggested to possess several extraribosomal functions, including an apoptotic function. In this study, we demonstrated that in the mouse brain, the protein
[...] Read more.
In addition to its role in ribosome biogenesis, ribosomal protein S3 (RPS3), a component of the 40S ribosomal subunit, has been suggested to possess several extraribosomal functions, including an apoptotic function. In this study, we demonstrated that in the mouse brain, the protein levels of RPS3 were altered by the degree of nutritional starvation and correlated with neuronal apoptosis. After endurable short-term starvation, the apoptotic function of RPS3 was suppressed by Akt activation and Akt-mediated T70 phosphorylation, whereas after prolonged starvation, the protein levels of RPS3 notably increased, and abundant neuronal death occurred. These events coincided with ubiquitination and subsequent degradation of RPS3, controlled by HSP70 and the cochaperone E3 ligase: carboxy terminus of heat shock protein 70-interacting protein (CHIP). Thus, our study points to an extraribosomal role of RPS3 in balancing neuronal survival or death depending on the degree of starvation through CHIP-mediated polyubiquitination and degradation. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Open AccessArticle AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro
Int. J. Mol. Sci. 2018, 19(8), 2295; https://doi.org/10.3390/ijms19082295
Received: 29 June 2018 / Revised: 1 August 2018 / Accepted: 3 August 2018 / Published: 5 August 2018
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Abstract
Brain-derived neurotrophic factor (BDNF) is one of the key signaling molecules that supports the viability of neural cells in various brain pathologies, and can be considered a potential therapeutic agent. However, several methodological difficulties, such as overcoming the blood–brain barrier and the short
[...] Read more.
Brain-derived neurotrophic factor (BDNF) is one of the key signaling molecules that supports the viability of neural cells in various brain pathologies, and can be considered a potential therapeutic agent. However, several methodological difficulties, such as overcoming the blood–brain barrier and the short half-life period, challenge the potential use of BDNF in clinical practice. Gene therapy could overcome these limitations. Investigating the influence of viral vectors on the neural network level is of particular interest because viral overexpression affects different aspects of cell metabolism and interactions between neurons. The present work aimed to investigate the influence of the adeno-associated virus (AAV)-Syn-BDNF-EGFP virus construct on neural network activity parameters in an acute hypobaric hypoxia model in vitro. Materials and methods. An adeno-associated virus vector carrying the BDNF gene was constructed using the following plasmids: AAV-Syn-EGFP, pDP5, DJvector, and pHelper. The developed virus vector was then tested on primary hippocampal cultures obtained from C57BL/6 mouse embryos (E18). Acute hypobaric hypoxia was induced on day 21 in vitro. Spontaneous bioelectrical and calcium activity of neural networks in primary cultures and viability tests were analysed during normoxia and during the posthypoxic period. Results. BDNF overexpression by AAV-Syn-BDNF-EGFP does not affect cell viability or the main parameters of spontaneous bioelectrical activity in normoxia. Application of the developed virus construct partially eliminates the negative hypoxic consequences by preserving cell viability and maintaining spontaneous bioelectrical activity in the cultures. Moreover, the internal functional structure, including the activation pattern of network bursts, the number of hubs, and the number of connections within network elements, is also partially preserved. BDNF overexpression prevents a decrease in the number of cells exhibiting calcium activity and maintains the frequency of calcium oscillations. Conclusion. This study revealed the pronounced antihypoxic and neuroprotective effects of AAV-Syn-BDNF-EGFP virus transduction in an acute normobaric hypoxia model. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Open AccessArticle Pharmacological Basis for the Use of Evodiamine in Alzheimer’s Disease: Antioxidation and Antiapoptosis
Int. J. Mol. Sci. 2018, 19(5), 1527; https://doi.org/10.3390/ijms19051527
Received: 7 May 2018 / Revised: 16 May 2018 / Accepted: 16 May 2018 / Published: 21 May 2018
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Abstract
Evodiamine (Evo), a major alkaloid compound isolated from the dry unripened fruit of Evodia fructus, has a wide range of pharmacological activities. The present study sought to explore the neuroprotective effects of Evo in l-glutamate (l-Glu)-induced apoptosis of HT22 cells,
[...] Read more.
Evodiamine (Evo), a major alkaloid compound isolated from the dry unripened fruit of Evodia fructus, has a wide range of pharmacological activities. The present study sought to explore the neuroprotective effects of Evo in l-glutamate (l-Glu)-induced apoptosis of HT22 cells, and in a d-galactose and aluminum trichloride-developed Alzheimer’s disease (AD) mouse model. Evo significantly enhanced cell viability, inhibited the accumulation of reactive oxygen species, ameliorated mitochondrial function, increased the B-cell lymphoma-2 protein content, and inhibited the high expression levels of Bax, Bad, and cleaved-caspase-3 and -8 in l-Glu-induced HT22 cells. Evo also enhanced the phosphorylation activities of protein kinase B and the mammalian target of rapamycin in the l-Glu-induced HT22 cells. In the AD mouse model, Evo reduced the aimless and chaotic movements, reduced the time spent in the central area in the open field test, and decreased the escape latency time in the Morris water maze test. Evo reduced the deposition of amyloid beta 42 (Aβ42) in the brain, and increased the serum level of Aβ42, but showed no significant effects on Aβ40. In addition, six weeks of Evo administration significantly suppressed oxidative stress by modulating the related enzyme levels. In the central cholinergic system of AD mice, Evo significantly increased the serum levels of acetylcholine and choline acetyltransferase and decreased the level of acetylcholinesterase in the serum, hypothalamus, and brain. Our results provide experimental evidence that Evo can serve as a neuroprotective candidate for the prevention and/or treatment of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Open AccessArticle Neuronal Dysfunction Associated with Cholesterol Deregulation
Int. J. Mol. Sci. 2018, 19(5), 1523; https://doi.org/10.3390/ijms19051523
Received: 17 April 2018 / Revised: 14 May 2018 / Accepted: 16 May 2018 / Published: 19 May 2018
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Abstract
Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase
[...] Read more.
Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith–Lemli–Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Open AccessArticle Protective Effects of Protocatechuic Acid on Seizure-Induced Neuronal Death
Int. J. Mol. Sci. 2018, 19(1), 187; https://doi.org/10.3390/ijms19010187
Received: 1 December 2017 / Revised: 26 December 2017 / Accepted: 3 January 2018 / Published: 8 January 2018
Cited by 1 | PDF Full-text (7527 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Protocatechuic acid (PCA) is a type of phenolic acid found in green tea and has been shown to have potent antioxidant and anti-inflammatory properties. However, the effect of PCA on pilocarpine seizure-induced neuronal death in the hippocampus has not been evaluated. In the
[...] Read more.
Protocatechuic acid (PCA) is a type of phenolic acid found in green tea and has been shown to have potent antioxidant and anti-inflammatory properties. However, the effect of PCA on pilocarpine seizure-induced neuronal death in the hippocampus has not been evaluated. In the present study, we investigated the potential therapeutic effects of PCA on seizure-induced brain injury. Epileptic seizure was induced by intraperitoneal (i.p.) injection of pilocarpine (25 mg/kg) in adult male rats, and PCA (30 mg/kg) was injected into the intraperitoneal space for three consecutive days after the seizure. Neuronal injury and oxidative stress were evaluated three days after a seizure. To confirm whether PCA increases neuronal survival and reduced oxidative injury in the hippocampus, we performed Fluoro-Jade-B (FJB) staining to detect neuronal death and 4-hydroxynonenal (4HNE) staining to detect oxidative stress after the seizure. In the present study, we found that, compared to the seizure vehicle-treated group, PCA administration reduced neuronal death and oxidative stress in the hippocampus. To verify whether a decrease of neuronal death by PCA treatment was due to reduced glutathione (GSH) concentration, we measured glutathione with N-ethylmaleimide (GS-NEM) levels in hippocampal neurons. A seizure-induced reduction in the hippocampal neuronal GSH concentration was preserved by PCA treatment. We also examined whether microglia activation was affected by the PCA treatment after a seizure, using CD11b staining. Here, we found that seizure-induced microglia activation was significantly reduced by the PCA treatment. Therefore, the present study demonstrates that PCA deserves further investigation as a therapeutic agent for reducing hippocampal neuronal death after epileptic seizures. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Review

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Open AccessReview Molecular Communication of a Dying Neuron in Stroke
Int. J. Mol. Sci. 2018, 19(9), 2834; https://doi.org/10.3390/ijms19092834
Received: 1 September 2018 / Revised: 14 September 2018 / Accepted: 15 September 2018 / Published: 19 September 2018
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Abstract
When a main artery of the brain occludes, a cellular response involving multiple cell types follows. Cells directly affected by the lack of glucose and oxygen in the neuronal core die by necrosis. In the periphery surrounding the ischemic core (the so-called penumbra)
[...] Read more.
When a main artery of the brain occludes, a cellular response involving multiple cell types follows. Cells directly affected by the lack of glucose and oxygen in the neuronal core die by necrosis. In the periphery surrounding the ischemic core (the so-called penumbra) neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells react to detrimental factors such as excitotoxicity, oxidative stress, and inflammation in different ways. The fate of the neurons in this area is multifactorial, and communication between all the players is important for survival. This review focuses on the latest research relating to synaptic loss and the release of apoptotic bodies and other extracellular vesicles for cellular communication in stroke. We also point out possible treatment options related to increasing neuronal survival and regeneration in the penumbra. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Open AccessReview Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors
Int. J. Mol. Sci. 2018, 19(8), 2280; https://doi.org/10.3390/ijms19082280
Received: 8 July 2018 / Revised: 26 July 2018 / Accepted: 31 July 2018 / Published: 3 August 2018
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Abstract
The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence
[...] Read more.
The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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Open AccessReview Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?
Int. J. Mol. Sci. 2018, 19(8), 2260; https://doi.org/10.3390/ijms19082260
Received: 26 June 2018 / Revised: 25 July 2018 / Accepted: 30 July 2018 / Published: 1 August 2018
Cited by 2 | PDF Full-text (2800 KB) | HTML Full-text | XML Full-text
Abstract
Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several
[...] Read more.
Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several lines of evidence have highlighted that HO-1 expression is associated to neuronal damage and neurodegeneration especially in Alzheimer’s and Parkinson’s diseases. In this review, we summarize the current literature regarding the role of HO-1 in nervous system pointing out different molecular mechanisms possibly responsible for HO-1 up-regulation in nervous system homeostasis and neurodegeneration. Full article
(This article belongs to the Special Issue Neuron Cell Death)
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