scholarly journals DTYMK is essential for genome integrity and neuronal survival

2021 ◽  
Author(s):  
Jo M. Vanoevelen ◽  
Jörgen Bierau ◽  
Janine C. Grashorn ◽  
Ellen Lambrichs ◽  
Erik-Jan Kamsteeg ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Genome Stability ◽  
Neuronal Survival ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cerebral Atrophy ◽  
Building Blocks ◽  
Acid Synthesis ◽  
Nucleotide Metabolism ◽  
Loss Of Function

AbstractNucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival.

scholarly journals Nonneuronal cells mediate neurotrophic action of vasoactive intestinal peptide.

1987 ◽  
Vol 104 (6) ◽  
pp. 1603-1610 ◽  
Author(s):  
D E Brenneman ◽  
E A Neale ◽  
G A Foster ◽  
S W d'Autremont ◽  
G L Westbrook
Keyword(s):  
Cell Death ◽  
Conditioned Medium ◽  
Vasoactive Intestinal Peptide ◽  
Neuronal Survival ◽  
Developmental Regulation ◽  
Protective Action ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Fibroblast Cultures ◽  
Spinal Cord Dorsal

The developmental regulation of neuronal survival by vasoactive intestinal peptide (VIP) was investigated in dissociated spinal cord-dorsal root ganglion (SC-DRG) cultures. Previous studies demonstrated that VIP increased neuronal survival in SC-DRG cultures when synaptic transmission was blocked with tetrodotoxin (TTX). This effect was further investigated to determine if VIP acted directly on neurons or via nonneuronal cells. For these studies, SC-DRG cells were cultured under conditions designed to provide preparations enriched for a particular cell type: astrocyte-enriched background cell (BG) cultures, meningeal fibroblast cultures, standard mixed neuron-nonneuron (STD) cultures, and neuron-enriched (N) cultures. Addition of 0.1 nM VIP to TTX-treated STD cultures for 5 d prevented the TTX-mediated death and the death that occurred naturally during development in culture, whereas the same treatment on N cultures did not prevent neuronal cell death. Conditioned medium from VIP-stimulated BG cultures prevented neuronal cell death when added to the medium (10% of total volume) of N cultures treated with TTX. The same amount of conditioned medium from BG cultures that were not treated with VIP had no protective action on N cultures. Conditioned medium from N or meningeal fibroblast cultures, either with or without VIP treatment, did not prevent TTX-mediated cell death in N test cultures. These data indicate that VIP increases the availability of neurotrophic survival-promoting substances derived from nonneuronal cultures, the most likely source being astroglial cells. This study suggests that VIP has a role in mediating a neuron-glia-neuron interaction that influences the trophic regulation of neuronal survival.

scholarly journals Adrenergic signaling in muscularis macrophages limits neuronal death following enteric infection

2019 ◽  
Author(s):  
Fanny Matheis ◽  
Paul A. Muller ◽  
Christina Graves ◽  
Ilana Gabanyi ◽  
Zachary J. Kerner ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Gastrointestinal Symptoms ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Enteric Infection ◽  
Loss Of Function ◽  
Arginase 1 ◽  
Irritable Bowel

SummaryEnteric–associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility. Bidirectional interactions between immune and neuronal cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated how infection-induced inflammation affects intrinsic EANs and the role of intestinalmuscularismacrophages (MMs) in this process. Using murine model of bacterial infection, we observed long-term gastrointestinal symptoms including reduced motility and subtype-specific neuronal loss. Neuronal-specific translational–profiling uncovered a caspase 11–dependent EAN cell–death mechanism induced by enteric infections. MMs responded to luminal infection by upregulating a neuroprotective program; gain– and loss–of-function experiments indicated that β2-adrenergic receptor (β2-AR) signaling in MMs mediates neuronal protection during infection via an arginase 1-polyamine axis. Our results identify a mechanism of neuronal cell death post–infection and point to a role for tissue–resident MMs in limiting neuronal damage.

scholarly journals Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1551
Author(s):  
Piergiorgio La Rosa ◽  
Sara Petrillo ◽  
Maria Teresa Fiorenza ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Cell Death ◽  
Neurodegenerative Disease ◽  
Neuronal Cell Death ◽  
Mitochondrial Protein ◽  
Neuronal Cell ◽  
Antioxidant Response ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Antioxidant Defenses ◽  
Special Focus

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

Mitochondria and Neuronal Survival

2000 ◽  
Vol 80 (1) ◽  
pp. 315-360 ◽  
Author(s):  
David G. Nicholls ◽  
Samantha L. Budd
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Neuronal Survival ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Oxygen Species ◽  
Inner Membrane ◽  
Isolated Mitochondria ◽  
Integral Role

Mitochondria play a central role in the survival and death of neurons. The detailed bioenergetic mechanisms by which isolated mitochondria generate ATP, sequester Ca2+, generate reactive oxygen species, and undergo Ca2+-dependent permeabilization of their inner membrane are currently being applied to the function of mitochondria in situ within neurons under physiological and pathophysiological conditions. Here we review the functional bioenergetics of isolated mitochondria, with emphasis on the chemiosmotic proton circuit and the application (and occasional misapplication) of these principles to intact neurons. Mitochondria play an integral role in both necrotic and apoptotic neuronal cell death, and the bioenergetic principles underlying current studies are reviewed.

scholarly journals POT1a depletion in the developing brain leads to p53-dependent neuronal cell death and ataxia

2018 ◽  
Author(s):  
Robert She ◽  
Charlie Clapp ◽  
Eros Lazzerini Denchi
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Progenitor ◽  
Damage Response ◽  
The Central Nervous System ◽  
P53 Inactivation ◽  
Dna Damage Response Pathway

AbstractThe processes that control genome stability are essential for the development of the Central Nervous System (CNS) and the prevention of neurological disease. Here we investigated whether activation of a DNA damage response by dysfunctional telomeres affects neurogenesis. More specifically, we analyzed ATR-dependent DNA damage response by depletion of POT1a in neural progenitors. These experiments revealed that POT1a inactivation leads to a partially penetrant lethality, and surviving mice displayed ataxia due to loss of neuronal progenitor cells, and died by 3 weeks of age. Inactivation of p53 was sufficient to completely suppress the lethality associated with POT1a depletion and rescued the neuronal defects characterizing POT1a depleted animals. In contrast, activation of ATM by the depletion of the shelterin protein TRF2 resulted in a fully penetrant lethality that could not be rescued by p53 inactivation (Lobanova et al.). This data reveals that activation of distinct types of DNA damage response pathway give rise to different types of neuropathology. Moreover, our data provides an explanation for the heterogeneity of the neurological defects observed in patients affected by telomere biological disorders.

scholarly journals Patients with obstructive sleep apnea have suppressed levels of soluble cytokine receptors involved in neurodegenerative disease, but normal levels with airways therapy

2020 ◽  
Author(s):  
Ye Wang ◽  
Richard B. Meagher ◽  
Suresh Ambati ◽  
Ping Ma ◽  
Bradley G. Phillips
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Neurodegenerative Disease ◽  
Intermittent Hypoxia ◽  
Statistical Significance ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cytokine Receptors ◽  
Healthy Controls ◽  
Obstructive Sleep

Abstract Purpose Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. Methods Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE). Results OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10−13 to 4 × 10−8). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10−13), IL6R (p = 1.1 × 10−9), TNFR1 (p = 2.5 × 10−10), and TNFR2 (p = 5.7 × 10−9), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. Conclusions Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients.

scholarly journals Why is NMNAT Protective against Neuronal Cell Death and Axon Degeneration, but Inhibitory of Axon Regeneration?

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 267 ◽  
Author(s):  
Bor Tang
Keyword(s):  
Axon Regeneration ◽  
Neuronal Survival ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Protein Translation ◽  
Phosphatase And Tensin Homolog ◽  
C Elegans ◽  
Tensin Homolog ◽  
Nad Synthesis ◽  
Key Enzyme

Nicotinamide mononucleotide adenylyltransferase (NMNAT), a key enzyme for NAD+ synthesis, is well known for its activity in neuronal survival and attenuation of Wallerian degeneration. Recent investigations in invertebrate models have, however, revealed that NMNAT activity negatively impacts upon axon regeneration. Overexpression of Nmnat in laser-severed Drosophila sensory neurons reduced axon regeneration, while axon regeneration was enhanced in injured mechanosensory axons in C. elegans nmat-2 null mutants. These diametrically opposite effects of NMNAT orthologues on neuroprotection and axon regeneration appear counterintuitive as there are many examples of neuroprotective factors that also promote neurite outgrowth, and enhanced neuronal survival would logically facilitate regeneration. We suggest here that while NMNAT activity and NAD+ production activate neuroprotective mechanisms such as SIRT1-mediated deacetylation, the same mechanisms may also activate a key axonal regeneration inhibitor, namely phosphatase and tensin homolog (PTEN). SIRT1 is known to deacetylate and activate PTEN which could, in turn, suppress PI3 kinase–mTORC1-mediated induction of localized axonal protein translation, an important process that determines successful regeneration. Strategic tuning of Nmnat activity and NAD+ production in axotomized neurons may thus be necessary to promote initial survival without inhibiting subsequent regeneration.

scholarly journals p21 inhibitor UC2288 ameliorates MPTP induced Parkinson’s disease progression through inhibition of oxidative stress and neuroinflammation

2020 ◽  
Author(s):  
Jun Hyung Im ◽  
In Jun Yeo ◽  
Seong Hee Jeon ◽  
Dong Hun Lee ◽  
Hyeon Joo Ham ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Neurodegenerative Disease ◽  
Dopaminergic Neurons ◽  
Kinase Inhibitor ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cultured Neurons ◽  
Dopamine Depletion ◽  
Erk Kinase

Abstract BackgroundParkinson's disease (PD) is a neurodegenerative disease characterized by the early prominent death of dopaminergic neurons and a decrease of dopamine levels. Dopamine depletion leads to several motor dysfunctions, including resting tremor, muscular rigidity, bradykinesia and postural instability. Our previous study determined that knockout of parkin, a gene of PD degrade p21, suppresses neurogenesis which is critical for a neurodegenerative disease. MethodsThus, we investigated the effect of UC2288, an inhibitor of p21, for its therapeutic effect on PD. We found that UC2288 attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in Rota-rod and Pole test as well as dopamine depletion.ResultsMoreover, UC2288 recovered the number of TH positive cells, but decreased the number of GFAP and Iba-1 positive cells accompanied the decrease of BAX and cleaved caspase3 as well as iNOS and COX-2 expression. In cultured neurons, UC2288 recovered MPP+-induced neuronal cell death in a concentration dependent manner. We also found that UC2288 decreased the p21 reactive cell number, oxidative neuronal damages, cytokines product in vivo and cultured neurons. In a mechanism study, we found that UC2288 significantly decreased the activation of ERK and p38 kinase pathway in the mitogen-activated protein kinase (MAPK) pathway. In addition, 1-10 μM concentration of ERK kinase inhibitor U0126 recovered MPP+-induced neuronal cell death. However, ERK kinase inhibitor U0126 further decreased cell viability with the increase of H2O2.ConclusionThese results indicated that the administration of UC2288 exerted neuroprotective effects on the death of dopaminergic neurons through the suppression of oxidative stress and neuroinflammation via ERK pathway inhibition.

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