Neuronal cell death in human neurodegenerative diseases and their animal/cell models

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

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Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling

Journal of Cellular and Molecular Medicine ◽

10.1111/j.1582-4934.2008.00402.x ◽

2008 ◽

Vol 12 (6a) ◽

pp. 2263-2280 ◽

Cited By ~ 144

Author(s):

Adrienne M. Gorman

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell

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Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004683117 ◽

2020 ◽

Vol 117 (52) ◽

pp. 33597-33607

Author(s):

Amit K. Patel ◽

Risa M. Broyer ◽

Cassidy D. Lee ◽

Tianlun Lu ◽

Mikaela J. Louie ◽

...

Keyword(s):

Cell Death ◽

Stem Cell ◽

Neurodegenerative Diseases ◽

Leucine Zipper ◽

Axon Regeneration ◽

Kinase Inhibitor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Term Survival ◽

Wide Range

Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that are known to both improve long-term survival and promote regeneration. To identify such a neuroprotective target, we conducted a set of complementary high-throughput screens using a protein kinase inhibitor library in human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds that promoted both neuroprotection and neurite outgrowth were bioinformatically deconvoluted to identify specific kinases that regulated neuronal death and axon regeneration. This work identified the role of germinal cell kinase four (GCK-IV) kinases in cell death and additionally revealed their unexpected activity in suppressing axon regeneration. Using an adeno-associated virus (AAV) approach, coupled with genome editing, we validated that GCK-IV kinase knockout improves neuronal survival, comparable to that of DLK knockout, while simultaneously promoting axon regeneration. Finally, we also found that GCK-IV kinase inhibition also prevented the attrition of RGCs in developing retinal organoid cultures without compromising axon outgrowth, addressing a major issue in the field of stem cell-derived retinas. Together, these results demonstrate a role for the GCK-IV kinases in dissociating the cell death and axonal outgrowth in neurons and their druggability provides for therapeutic options for neurodegenerative diseases.

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The Potential for Natural Antioxidant Supplementation in the Early Stages of Neurodegenerative Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21072618 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2618 ◽

Cited By ~ 7

Author(s):

Francesca Oppedisano ◽

Jessica Maiuolo ◽

Micaela Gliozzi ◽

Vincenzo Musolino ◽

Cristina Carresi ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Antioxidant Compounds ◽

Pathophysiological Mechanisms ◽

Early Stages ◽

Neurodegenerative Process ◽

The Central Nervous System ◽

Potential Strategy

The neurodegenerative process is characterized by the progressive ultrastructural alterations of selected classes of neurons accompanied by imbalanced cellular homeostasis, a process which culminates, in the later stages, in cell death and the loss of specific neurological functions. Apart from the neuronal cell impairment in selected areas of the central nervous system which characterizes many neurodegenerative diseases (e.g., Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, etc.), some alterations may be found in the early stages including gliosis and the misfolding or unfolding accumulation of proteins. On the other hand, several common pathophysiological mechanisms can be found early in the course of the disease including altered oxidative metabolism, the loss of cross-talk among the cellular organelles and increased neuroinflammation. Thus, antioxidant compounds have been suggested, in recent years, as a potential strategy for preventing or counteracting neuronal cell death and nutraceutical supplementation has been studied in approaching the early phases of neurodegenerative diseases. The present review will deal with the pathophysiological mechanisms underlying the early stages of the neurodegenerative process. In addition, the potential of nutraceutical supplementation in counteracting these diseases will be assessed.

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Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6565396 ◽

2020 ◽

Vol 2020 ◽

pp. 1-30 ◽

Cited By ~ 6

Author(s):

Nur Shafika Mohd Sairazi ◽

K. N. S. Sirajudeen

Keyword(s):

Cell Death ◽

Natural Products ◽

Neurodegenerative Diseases ◽

Bioactive Compounds ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuronal Structure ◽

And Function

In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.

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Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19103082 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3082 ◽

Cited By ~ 41

Author(s):

Hao Chi ◽

Hui-Yun Chang ◽

Tzu-Kang Sang

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Alpha Synuclein ◽

Adult Brain ◽

Pathological Feature ◽

The Central Nervous System ◽

Cell Death Mechanisms ◽

The Brain

Neuronal cell death in the central nervous system has always been a challenging process to decipher. In normal physiological conditions, neuronal cell death is restricted in the adult brain, even in aged individuals. However, in the pathological conditions of various neurodegenerative diseases, cell death and shrinkage in a specific region of the brain represent a fundamental pathological feature across different neurodegenerative diseases. In this review, we will briefly go through the general pathways of cell death and describe evidence for cell death in the context of individual common neurodegenerative diseases, discussing our current understanding of cell death by connecting with renowned pathogenic proteins, including Tau, amyloid-beta, alpha-synuclein, huntingtin and TDP-43.

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Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production

Natural Product Communications ◽

10.1177/1934578x19896684 ◽

2019 ◽

Vol 14 (12) ◽

pp. 1934578X1989668 ◽

Cited By ~ 1

Author(s):

Phil Jun Lee ◽

Hye-Jin Park ◽

Hee Min Yoo ◽

Namki Cho

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Er Stress ◽

Heme Oxygenase ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ros Generation ◽

Heme Oxygenase 1 ◽

Ros Scavenging ◽

Neuroprotective Effects

A key pathologic event in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, is endoplasmic reticulum (ER) stress-induced neuronal cell death. ER stress-induced generation of reactive oxygen species (ROS) has been implicated in neurological disease processes. Betulin is one of the major triterpenoids found in Betula platyphylla that possesses several biological properties, including cytoprotective and antioxidative effects. Therefore, we investigated whether betulin could prevent ER stress-induced neurotoxicity in HT-22 hippocampal neuronal cells. We observed that betulin reduced the thapsigargin (TG, an ER stress inducer)-induced apoptosis of HT-22 cells. Moreover, the cytoprotective effects of betulin were comparable to those of tauroursodeoxycholic acid, a potent ER stress-reducing agent. In our study, we confirmed that the ER stress-induced accumulation of ROS plays an important role in HT-22 cell death. Betulin also displayed cytoprotective effects in TG-injured HT-22 cells by reducing ROS generation; these results were comparable to those for N-acetyl-L-cysteine, a known ROS inhibitor. In addition, SnPP, a heme oxygenase-1 (HO-1) inhibitor significantly blocked the cytoprotective effects and ROS scavenging activity of betulin. Based on these results, we believe that betulin-mediated induction of HO-1 may contribute to the neuroprotective effects against ER stress in HT-22 hippocampal cells. We also found that betulin significantly inhibited the TG-induced expression of CHOP and caspase-12. These results demonstrated that betulin could serve as a potential therapeutic agent against ER stress-induced neurodegenerative diseases.

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Comprehensive Insight of Neurodegenerative Diseases and The Role of Neurotoxin Agents — Glutamate

Progress In Microbes & Molecular Biology ◽

10.36877/pmmb.a0000070 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Hui-Min Yap ◽

Kwan-Liang Lye ◽

Loh Teng-Hern Tan

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neurodegenerative Diseases ◽

Monosodium Glutamate ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Glutamate Excitotoxicity ◽

Glutamate Toxicity ◽

Extracellular Glutamate

The increased concentration of extracellular glutamate has been reported to play a key role in most of the neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, even though its importance as an amino acid neurotransmitter in mammalian. Glutamate toxicity, which can be caused by excessive intake of monosodium glutamate (MSG), is the major contributor to pathological neuronal cell death. It causes neuronal dysfunction and degeneration in the central nervous system (CNS). Glutamate neurotoxicity can be categorized into two forms, which are receptor-mediated glutamate excitotoxicity and non-receptor mediated glutamate oxidative toxicity. The receptor-mediated glutamate excitotoxicity involved excessive stimulation of glutamate receptors (GluRs) which lead to excessive ion calcium (Ca2+) influx and activates a cell death cascade involving the accumulation of mitochondrially generated reactive oxygen species (ROS). Studies showed excessive extracellular glutamate leads to nerve cell death via the activation of N-methyl-Daspartate (NMDA) receptors in the cases of trauma or stroke. Whereas non-receptor mediated oxidative toxicity involved the breakdown of the cystine/glutamate antiporter (xc - ) mechanism, which leads to the depletion of glutathione (GSH) and causes oxidative stress and cell death. The cystine/glutamate antiporter couples the import of cystine to the export of glutamate. The increased concentration of extracellular glutamate could inhibit the uptake of cystine, which is required for the synthesis of the intracellular antioxidant GSH. GSH plays an important role in the disposal of peroxides by brain cells and in the protection against ROS. Depletion of GSH renders the cell to oxidative stress and ultimately leading to cell death. This article aims to provide a comprehensive review of neurodegenerative diseases and the role of neurotoxin agents, glutamate in these diseases.

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Air Pollution-Related Brain Metal Dyshomeostasis as a Potential Risk Factor for Neurodevelopmental Disorders and Neurodegenerative Diseases

Atmosphere ◽

10.3390/atmos11101098 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1098

Author(s):

Deborah Cory-Slechta ◽

Marissa Sobolewski ◽

Günter Oberdörster

Keyword(s):

Oxidative Stress ◽

Air Pollution ◽

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Neurodevelopmental Disorders ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Autism Spectrum ◽

System Structure

Increasing evidence links air pollution (AP) exposure to effects on the central nervous system structure and function. Particulate matter AP, especially the ultrafine (nanoparticle) components, can carry numerous metal and trace element contaminants that can reach the brain in utero and after birth. Excess brain exposure to either essential or non-essential elements can result in brain dyshomeostasis, which has been implicated in both neurodevelopmental disorders (NDDs; autism spectrum disorder, schizophrenia, and attention deficit hyperactivity disorder) and neurodegenerative diseases (NDGDs; Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis). This review summarizes the current understanding of the extent to which the inhalational or intranasal instillation of metals reproduces in vivo the shared features of NDDs and NDGDs, including enlarged lateral ventricles, alterations in myelination, glutamatergic dysfunction, neuronal cell death, inflammation, microglial activation, oxidative stress, mitochondrial dysfunction, altered social behaviors, cognitive dysfunction, and impulsivity. Although evidence is limited to date, neuronal cell death, oxidative stress, and mitochondrial dysfunction are reproduced by numerous metals. Understanding the specific contribution of metals/trace elements to this neurotoxicity can guide the development of more realistic animal exposure models of human AP exposure and consequently lead to a more meaningful approach to mechanistic studies, potential intervention strategies, and regulatory requirements.

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