Endoplasmic reticulum stress contributes to the decline in doublecortin expression in the immature neurons of mice with long-term obesity.
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ABSTRACT:
SUBMITTER: Nakagawa K
PROVIDER: S-EPMC8770636 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose: We investigated Nr4a effector genes following a hippocampus dependent learning task using a dominant mouse model of Nr4a. Method: We performed total RNA sequencing after training for hippocampus-dependent memory from Nr4ADN and control littermates Results: Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we found that Nr4a transcription factors regulate expression of specific effector genes encoding endoplasmic reticulum (ER) chaperones that drive protein folding, enabling membrane proteins to more efficiently traffic to the cell surface. Conclusion: This study identified the effector genes of Nr4a transcription factors involved in learning and memory.
2021-03-01 | GSE167566 | GEO
Project description:It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.
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Project description:Phosphoinositide 3-kinase ? (PI3K?) expressed in immune cells is linked to neuroinflammation in several neurological diseases. However, the expression and role of PI3K? in preclinical traumatic brain injury (TBI) have not been investigated. In WT mice, we found that TBI induced rapid and extensive expression of PI3K? in neurons within the perilesional cortex and the ipsilateral hippocampal subfields (CA1, CA3), which peaked between 1 and 3 days and declined significantly 7 days after TBI. Intriguingly, the induction of neuronal PI3K? in these subregions of the brain spatiotemporally coincided with both the TBI-induced activation of the neuronal ER stress pathway (p-eIF2?, ATF4, and CHOP) and neuronal cell death (marked by TUNEL-positive neurons) 3 days after TBI. Further, we show that the absence of PI3K? in knockout mice profoundly reduced the TBI-induced activation of the ER stress pathway and neuronal cell death. White matter disruption is a better predictor of long-term clinical outcomes than focal lesion size. We show that PI3K? deficiency not only reduced brain tissue loss but also alleviated white matter injury (determined by axonal injury and demyelination) up to 28 days after TBI. Importantly, PI3K?-knockout mice exhibited greater functional recovery including forepaw use, sensorimotor balance and coordination, and spatial learning and memory up to 28 days after TBI. These results unveil a previously unappreciated role for neuronal PI3K? in the regulation of ER stress associated with neuronal cell death, white matter damage, and long-term functional impairment after TBI.
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Project description:DCX-immunoreactive (DCX+) cells occur in the piriform cortex in adult mice and rats, but also in the neocortex in adult guinea pigs and rabbits. Here we describe these cells in adult domestic cats and primates. In cats and rhesus monkeys, DCX+ cells existed across the allo- and neocortex, with an overall ventrodorsal high to low gradient at a given frontal plane. Labeled cells formed a cellular band in layers II and upper III, exhibiting dramatic differences in somal size (5-20 microm), shape (unipolar, bipolar, multipolar and irregular), neuritic complexity and labeling intensity. Cell clusters were also seen in this band, and those in the entorhinal cortex extended into deeper layers as chain-like structures. Densitometry revealed a parallel decline of the cells across regions with age in cats. Besides the cellular band, medium-sized cells with weak DCX reactivity resided sparsely in other layers. Throughout the cortex, virtually all DCX+ cells co-expressed polysialylated neural cell adhesion molecule. Medium to large mature-looking DCX+ cells frequently colocalized with neuron-specific nuclear protein and gamma-aminobutyric acid (GABA), and those with a reduced DCX expression also partially co-labeled for glutamic acid decarboxylase, parvalbumin, calbindin, beta-nicotinamide adenine dinucleotide phosphate diaphorase and neuronal nitric oxide synthase. Similar to cats and monkeys, small and larger DCX+ cells were detected in surgically removed human frontal and temporal cortices. These data suggest that immature neurons persist into adulthood in many cortical areas in cats and primates, and that these cells appear to undergo development and differentiation to become functional subgroups of GABAergic interneurons.
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Project description:Aquaporin-11 (AQP11) is expressed in human adipocytes, but its functional role remains unknown. Since AQP11 is an endoplasmic reticulum (ER)-resident protein that transports water, glycerol, and hydrogen peroxide (H2O2), we hypothesized that this superaquaporin is involved in ER stress induced by lipotoxicity and inflammation in human obesity. AQP11 expression was assessed in 67 paired visceral and subcutaneous adipose tissue samples obtained from patients with morbid obesity and normal-weight individuals. We found that obesity and obesity-associated type 2 diabetes increased (p < 0.05) AQP11 mRNA and protein in visceral adipose tissue, but not subcutaneous fat. Accordingly, AQP11 mRNA was upregulated (p < 0.05) during adipocyte differentiation and lipolysis, two biological processes altered in the obese state. Subcellular fractionation and confocal microscopy studies confirmed its presence in the ER plasma membrane of visceral adipocytes. Proinflammatory factors TNF-?, and particularly TGF-?1, downregulated (p < 0.05) AQP11 mRNA and protein expression and reinforced its subcellular distribution surrounding lipid droplets. Importantly, the AQP11 gene knockdown increased (p < 0.05) basal and TGF-?1-induced expression of the ER markers ATF4 and CHOP. Together, the downregulation of AQP11 aggravates TGF-?1-induced ER stress in visceral adipocytes. Owing to its "peroxiporin" properties, AQP11 overexpression in visceral fat might constitute a compensatory mechanism to alleviate ER stress in obesity.
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Project description:Vacuolating cytotoxin A (VacA) is one of the important virulence factors produced by H. pylori. VacA induces apoptotic cell death, which is potentiated by ammonia. VacA also causes cell death by mitochondrial damage, via signaling pathways that are not fully defined. Our aim was to determine whether endoplasmic reticulum (ER) stress is associated with VacA-induced mitochondrial dysfunction and apoptosis. We found that C/EBP homologous protein (CHOP), a key signaling protein of ER stress-induced apoptosis, was transcriptionally up-regulated following incubation of gastric epithelial cells with VacA. The effect of VacA on CHOP induction was significantly enhanced by co-incubation with ammonium chloride. Phosphorylation of eukaryotic initiation factor 2 (eIF2)-alpha, which is known to occur downstream of the ER stress sensor PKR-like ER-localized eIF2-alpha kinase (PERK) and to regulate CHOP expression, was also observed following incubation with VacA in the presence of ammonium chloride. Knockdown of CHOP by siRNA resulted in inhibition of VacA-induced apoptosis. Further studies showed that silencing of the PERK gene with siRNA attenuated VacA-mediated phosphorylation of eIF2-alpha, CHOP induction, expression of BH3-only protein Bim and Bax activation, and cell death induced by VacA with ammonium chloride, indicating that ER stress may lead to mitochondrial dysfunction during VacA-induced toxicity. Activation of ER stress and up-regulation of BH3-only proteins were also observed in human H. pylori-infected gastric mucosa. Collectively, this study reveals a possible association between VacA-induced apoptosis in gastric epithelial cells, and activation of ER stress in H. pylori-positive gastric mucosa.
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Project description:Prior research has demonstrated cells exposed to silver nanoparticles (AgNPs) undergo endoplasmic reticulum (ER) stress leading to cellular apoptosis and toxicity, however, the fundamental mechanism underlying AgNP-induced ER stress is unknown. We hypothesize the biophysical interactions between AgNPs and adsorbed proteins lead to misfolded proteins to elicit an ER stress response. Our investigation examined rat aortic endothelial cells (RAEC) exposed to 20 or 100 nm AgNPs with or without a biocorona (BC) consisting of bovine serum albumin (BSA), high density lipoprotein (HDL) or fetal bovine serum (FBS) to form a complex BC. The presence of a BC consisting of BSA or FBS proteins significantly reduced uptake of 20 nm and 100 nm AgNPs in RAEC. Western blot analysis indicated robust activation of the IREα and PERK pathways in RAEC exposed to 20 nm despite the reduction in uptake by the presence of a BC. This was not observed for the 100 nm AgNPs. Hyperspectral darkfield microscopy qualitatively confirmed that the preformed BC was maintained following uptake by RAEC. Transmission electron microscopy demonstrated a size dependent effect on the sub-cellular localization of AgNPs. Overall, these results suggest that AgNP size, surface area and BC formation governs the induction of ER stress and alterations in intracellular trafficking.
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Project description:In thin sections of cells infected with vaccinia virus or other poxviruses, the viral membrane is first discerned as a crescent or circle lacking obvious continuity with a cellular organelle, presenting an appearance of de novo membrane biogenesis. This notion, which many consider heretical, is nevertheless consistent with the absence of a signature of endoplasmic reticulum (ER) trafficking, such as signal peptide cleavage or glycosylation, in any of the numerous viral membrane proteins. The purpose of this study was to determine whether an operative pathway exists between the ER and the immature virion membrane. We showed that the highly conserved A9 viral membrane protein was inserted into the ER of uninfected cells with the same topology as in viral membranes. Next, we found that replacement of the nonessential cytoplasmic tail of A9 with one containing COPII-binding sites reduced incorporation of the modified A9 into viral membranes and led to its accumulation in the Golgi apparatus, implying that A9 was inserted into the ER and then diverted from its natural path. Most importantly, we demonstrated cleavage of a heterologous signal peptide fused to the N-terminal region of A9 and localized the truncated protein in immature and mature virions. Additionally, immunoelectron micrographs showed A9 in tubules containing protein disulfide isomerase, an ER lumenal protein, near immature viral membranes. The present data provide strong evidence for an operative pathway from ER domains within the virus factory to the viral membrane.
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Project description:mGluR long-term depression (mGluR-LTD) is a form of synaptic plasticity induced at excitatory synapses by metabotropic glutamate receptors (mGluRs). mGluR-LTD reduces synaptic strength and is relevant to learning and memory, autism, and sensitization to cocaine; however, the mechanism is not known. Here we show that activation of Group I mGluRs in medium spiny neurons induces trafficking of GluA2 from the endoplasmic reticulum (ER) to the synapse by enhancing GluA2 binding to essential COPII vesicle proteins, Sec23 and Sec13. GluA2 exit from the ER further depends on IP3 and Ryanodine receptor-controlled Ca2+ release as well as active translation. Synaptic insertion of GluA2 is coupled to removal of high-conducting Ca2+-permeable AMPA receptors from synapses, resulting in synaptic depression. This work demonstrates a novel mechanism in which mGluR signals release AMPA receptors rapidly from the ER and couple ER release to GluA2 synaptic insertion and GluA1 removal.
| S-EPMC5239995 | biostudies-literature
Project description:PURPOSE:To investigate the mechanism of ? receptor 1 (?R1) neuroprotection in retinal neurons. METHODS:Oxidative stress, which is implicated in diabetic retinopathy, was induced in mouse primary ganglion cells (GCs) and RGC-5 cells, and the effect of the ?R1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of ?R1 to BiP, an ER chaperone protein, and ?R1 phosphorylation status were examined by immunoprecipitation. Retinas were harvested from Ins2Akita/+ diabetic mice treated with (+)-pentazocine, and the expression of ER stress genes and of the retinal transcriptome was evaluated. RESULTS:Oxidative stress induced the death of primary GCs and RGC-5 cells. The effect was decreased by the application of (+)-pentazocine. Stress increased ?R1 binding to BiP and enhanced ?R1 phosphorylation in RGC-5 cells. BiP binding was prevented, and ?R1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1?, and CHOP were upregulated in RGC-5 cells during oxidative stress, but decreased in the presence of (+)-pentazocine. A similar phenomenon was observed in retinas of Ins2Akita/+ diabetic mice. Retinal transcriptome analysis of Ins2Akita/+ mice compared with wild-type revealed differential expression of the genes critically involved in oxidative stress, differentiation, and cell death. The expression profile of those genes was reversed when the Ins2Akita/+ mice were treated with (+)-pentazocine. CONCLUSIONS:In retinal neurons, the molecular chaperone ?R1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating ?R1 from BiP. As stress in retinal cells increases, phosphorylation of ?R1 is increased, which is attenuated when agonists bind to the receptor.
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