Inhibition of cytoplasmic p53 differentially modulates Ca2+ signaling and cellular viability in young and aged striata

Ureshino, Rodrigo Portes; Hsu, Yi‐Te; Carmo, Lúcia Garcez do; Yokomizo, César H.; Nantes, Iseli L.; Smaili, Soraya Soubhi

doi:10.1016/j.exger.2014.07.014

Cited by 7 publications

(11 citation statements)

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“…Indeed, overstimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate can produce massive Ca 2+ entry, which is taken up by mitochondria and leads to excitotoxicity [43]. NMDA overactivation may contribute to altered Ca 2+ homeostasis in neurodegenerative diseases [42, 44, 45]. The data reported in this study indicate that a low concentration of glutamate stimulates autophagy and acts as a pro-survival mechanism under physiological conditions.…”

Section: Discussionmentioning

confidence: 93%

“…It was demonstrated that hyperammonemia can increase the autophagy markers such as beclin-1, LC3II and p62 and contributes to muscle loss in sarcopenia with cirrhosis condition [40]. By contrast, a high concentration of glutamate leads progressively to cell death by apoptosis or other death mechanisms [41, 42]. Indeed, overstimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate can produce massive Ca 2+ entry, which is taken up by mitochondria and leads to excitotoxicity [43].…”

Section: Discussionmentioning

confidence: 99%

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Glutamate induces autophagy via the two-pore channels in neural cells

et al. 2016

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NAADP (nicotinic acid adenine dinucleotide phosphate) has been proposed as a second messenger for glutamate in neuronal and glial cells via the activation of the lysosomal Ca2+ channels TPC1 and TPC2. However, the activities of glutamate that are mediated by NAADP remain unclear. In this study, we evaluated the effect of glutamate on autophagy in astrocytes at physiological, non-toxic concentration. We found that glutamate induces autophagy at similar extent as NAADP. By contrast, the NAADP antagonist NED-19 or SiRNA-mediated inhibition of TPC1/2 decreases autophagy induced by glutamate, confirming a role for NAADP in this pathway. The involvement of TPC1/2 in glutamate-induced autophagy was also confirmed in SHSY5Y neuroblastoma cells. Finally, we show that glutamate leads to a NAADP-dependent activation of AMPK, which is required for autophagy induction, while mTOR activity is not affected by this treatment. Taken together, our results indicate that glutamate stimulates autophagy via NAADP/TPC/AMPK axis, providing new insights of how Ca2+ signalling glutamate-mediated can control the cell metabolism in the central nervous system.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Glutamate induces autophagy via the two-pore channels in neural cells

et al. 2016

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“…28 , 32 , 33 Recent studies have shown that an increase in p53 or Bax often corresponds to reduce cell viability through the modulation of calcium signaling in mitochondria-linked apoptosis. 34 , 35 Bax is central to the “suggested” p53 -motochondria apoptotic pathway by directing ROS-induced calcium-shift through its ability to increase mitochondria membrane permeability. 34 – 36 A major comparison is the role of Bax as a calcium transport regulator in oxidative stress 36 versus its role as a cell cycle exit protein in death of olfactory bulb neurons (apoptosis).…”

Section: Discussionmentioning

confidence: 99%

Bax modulates neuronal survival while p53 is unaltered after Cytochrome C induced oxidative stress in the adult olfactory bulb in vivo

Ogundele¹,

Sanya

2015

ANS

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BackgroundThe granule and periglomerular cells of the olfactory bulb migrate from the sub-ventricular zone (SVZ) as progenitor cell forming the neuronal stream of the rostral olfactory bulb. These cells are characterized by their ability to divide while expressing adult proteins; a phenomenon attributed to the prolonged cell cycle and the regulatory activities of proteins which modulates apoptosis and proliferation in the developing nervous system. Of interest are the proteins concerned with tumor suppression (p53) and cell cycle exit (Bax) and how they regulate survivability of these neurons in the adult system after an induced oxidative stress.PurposeThis study sets to investigate the interplay between p53 and Bax in the adult olfactory bulb (periglomerular and granule cell layer), and how these proteins determine proliferation and neuronal survival after Cytochrome C induced-oxidative stress. Also, we demonstrate the effect of the induced-stress threshold on such regulation in vivo.MethodsAdult Wistar rats were segregated into three groups. 10 and 20 mg/Kg BW of potassium cyanide (KCN) was administered to the treatment groups for 15 days while the control received normal saline for the same duration. The olfactory bulb was dissected and processed for general histology and immunohistochemistry of p53/Bax in the periglomerular and granule cell layers. Total (Histology) and immunopositive (p53 and Bax) cell count was done using Image J. Subsequently, we determined the analysis of variance with significance set at *P<0.05.ResultsWe observed an increase in cell count for the 10 mg/KgBW treatment; this was characterized by a significant decrease in Bax expression and no change in p53 expression when this treatment group was compared to the control. However, no change was observed in the total cell count for 20 mg/Kg BW treatment for the same duration of exposure. Interestingly, there was also no significant change in Bax and p53 for this treatment when compared with the control.ConclusionAlthough p53 plays an important role in development of the olfactory bulb neurons, our findings suggests it has little contribution in neuronal cell viability and proliferation in the adult olfactory bulb. No significant change in p53 was observed irrespective of treatment dose and cell count while Bax expression was reduced at 10 mg/Kg BW treatment and was associated with an increased cell count. We conclude that regulation of survival of neurons in the adult olfactory bulb, following induced-oxidative stress was more dependent of the expression of Bax and the threshold of the induced stress rather than p53 expression.

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“…For this experiment, animals used in the behavior experiments were euthanized by decapitation, the skull was gently opened, and the brain was rapidly removed. Brains were immersed in an artificial cerebral-spinal fluid (aCSF) solution (2 mM KCl, 1 mM CaCl 2 , 26 mM NaHCO 3 , 1.25 mM NaH 2 PO 4 , 1 mM MgCl 2 , 2 mM MgSO 4 , 10 mM glucose, 248 mM sucrose, and pH 7.4; Ureshino et al 2014) and then sliced in a vibratome, into sagittal sections (*2.5 mm thick) containing the striatum and midbrain. Slices were fixed in 4% paraformaldehyde (w/v) in 0.1 M phosphate buffered saline (PBS), followed by cryoprotection with a 20% sucrose solution (w/v) in PBS at room temperature, overnight.…”

Section: Behavior Test and Semiquantification Of Tyrosine Hydroxylasementioning

confidence: 99%

“…Animals were euthanized, and the brains were rapidly and gently removed. Afterward, the brains were sliced in a vibratome (approximately 400 mM thick), immersed into a sucrose-supplemented aCSF solution (2 mM KCl, 1 mM CaCl 2 , 26 mM NaHCO 3 , 1.25 mM NaH 2 PO 4 , 1 MgCl 2 , 2 mM MgSO 4 , 10 mM glucose, 248 mM sucrose, and pH 7.4) and then incubated in normal aCSF solution (2 mM KCl, 2 mM CaCl 2 , 26 mM NaHCO 3 , 1.25 mM NaH 2 PO 4 , 2 mM MgSO 4 , 10 mM glucose, 124 mM NaCl, and pH 7.4; Ureshino et al 2014). The solution was perfused and constantly aerated in a vibratome and maintained at room temperature.…”

Section: Ros Measurementsmentioning

confidence: 99%

Effects of Aging in the Striatum and Substantia Nigra of a Parkinson’s Disease Animal Model

et al. 2018

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Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson's disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological models, but due to the limitations of the animal models, particularly in aged animals, the results are difficult to interpret. In this work, we investigated neurodegeneration induced by rotenone, as a pharmacological model of Parkinson's disease, in both young and aged Wistar rats. We assessed animal mobility, tyrosine hydroxylase staining in the substantia nigra pars compacta (SNpc), and TdT-mediated dUTP-biotin nick end labeling-positive nuclei and reactive oxygen species production in the striatum. Interestingly, the mobility impairment, dopaminergic neuron loss, and elevated number of apoptotic nuclei in the striatum of aged control rats were similar to young rotenone-treated animals. Moreover, we observed many ultrastructural alterations, such as swollen mitochondria in the striatum, and massive lipofuscin deposits in the SNpc of the aged rotenone-treated animals. We conclude that the rotenone model can be employed to explore age-related alterations in the ontogeny that can increase vulnerability in the striatum and SNpc, which may contribute to Parkinson's disease pathogenesis.

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Inhibition of cytoplasmic p53 differentially modulates Ca2+ signaling and cellular viability in young and aged striata

Cited by 7 publications

References 52 publications

Glutamate induces autophagy via the two-pore channels in neural cells

Glutamate induces autophagy via the two-pore channels in neural cells

Bax modulates neuronal survival while p53 is unaltered after Cytochrome C induced oxidative stress in the adult olfactory bulb in vivo

Effects of Aging in the Striatum and Substantia Nigra of a Parkinson’s Disease Animal Model

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