scholarly journals Amyloid Beta Oligomers Prevents Lysosomal Targeting of miRNP to Stop Its Recycling and Target Cytokine Repression in Glial Cells

2020 ◽  
Author(s):  
Dipayan De ◽  
Suvendra N. Bhattacharyya
Keyword(s):  
Endoplasmic Reticulum ◽  
Glial Cells ◽  
Amyloid Beta ◽  
De Novo ◽  
List Type ◽  
P Bodies ◽  
Mrna Targets ◽  
Lysosomal Targeting ◽  
Processing Body ◽  
Endosome Maturation

AbstractmRNAs encoding inflammatory cytokines are targeted by miRNAs and remain repressed in neuroglial cells. On exposure to amyloid beta 1-42 oligomers, glial cells start expressing proinflammatory cytokines although there has been increase in repressive miRNAs levels as well. Exploring the mechanism of this potential immunity of target cytokine mRNAs against repressive miRNAs in amyloid beta exposed glial cells, we have identified differential compartmentalization of repressive miRNAs in glial cells to explain this aberrant miRNA function. While the target mRNAs were found to be associated with polysomes attached to endoplasmic reticulum, the miRNPs found to be present predominantly with endosomes that failed to recycle to endoplasmic reticulum attached polysomes to repress mRNA targets in treated cells. Amyloid beta oligomers, by masking the Rab7 proteins on endosomal surface, affects Rab7 interaction with Rab Interacting Lysosomal Protein (RILP) on lysosomes to restrict endosomal maturation and its lysosomal targeting. This causes retarded miRNP targeting to lysosomes and recycling. Similar defects in miRNP retrieval has been observed in endosome maturation defective cells depleted for RILP or treated with Bafilomycin. RNA processing body localization of the miRNPs was also noted in treated cells that happens as a consequence of enhanced endosomal retention of miRNPs. Interestingly, depletion of P-body partly rescues the miRNA function in glial cells exposed to amyloid beta and restricts the excess cytokine expression there.Graphical AbstractKey PointsAmyloid beta exposure causes accumulation of inactive miR-146 miRNP to cause elevated proinflammatory cytokine production in glial cells.Amyloid beta masks Rab7-RILP interaction to reduce endosome lysosome interaction.Accumulated miRNPs failed to get targeted to lysosomes in amyloid exposed cells due to loss of endosome lysosome interactionLysosomal compartmentalization of miRNPs is required for its recycling and repression of de novo targetsAccumulated miRNPs are stored in P-Bodies and depletion of P-Bodies rescues miRNA function in amyloid exposed glial cells.

scholarly journals Amyloid Beta oligomers prevents Lysosomal targeting of miRNP to stop its recycling and target repression in glial cells

2021 ◽  
Author(s):  
Dipayan De ◽  
Suvendra N. Bhattacharyya
Keyword(s):  
Endoplasmic Reticulum ◽  
Glial Cells ◽  
Amyloid Beta ◽  
Rna Processing ◽  
Mrna Targets ◽  
Lysosomal Targeting ◽  
Body Components ◽  
Processing Body ◽  
Cytokine Mrnas ◽  
Lysosomal Protein

On exposure to Amyloid Beta Oligomers (Aβ1-42), glial cells start expressing proinflammatory cytokines although there has been increase in repressive miRNAs levels as well. Exploring the mechanism of this potential immunity of target cytokine mRNAs against repressive miRNAs in amyloid beta exposed glial cells, we have identified differential compartmentalization of repressive miRNAs in glial cells to explain this aberrant miRNA function. While the target mRNAs were found to be associated with polysomes attached to endoplasmic reticulum, the miRNPs found to be present predominantly with endosomes that failed to recycle to endoplasmic reticulum attached polysomes to repress mRNA targets in Aβ1-42 treated cells. Aβ1-42 oligomers, by masking the Rab7 proteins on endosomal surface, affects Rab7 interaction with Rab Interacting Lysosomal Protein (RILP) to restrict lysosomal targeting and recycling of miRNPs. RNA processing body or P-body localization of the miRNPs also get enhanced in amyloid beta treated cells as a consequence of enhanced endosomal retention of miRNPs. Interestingly, depletion of P-body components partly rescues the miRNA function in glial cells exposed to amyloid beta and restricts the excess cytokine expression there.

Modification of Pineal Ultrastructure by Exogenous Hormones

1967 ◽  
Vol 25 ◽  
pp. 170-171
Author(s):  
R. A. Turner ◽  
A. E. Rodin ◽  
D. K. Roberts
Keyword(s):  
Electron Microscopy ◽  
Endoplasmic Reticulum ◽  
Rough Endoplasmic Reticulum ◽  
Estradiol Benzoate ◽  
Female Rats ◽  
List Type ◽  
Type Number ◽  
Pregnant Rats ◽  
Gonadal Atrophy ◽  
Pineal Ultrastructure

There have been many reports which establish a relationship between the pineal and sexual structures, including gonadal hypertrophy after pinealectomy, and gonadal atrophy after injection of pineal homogenates or of melatonin. In order to further delineate this relationship the pineals from 5 groups of female rats were studied by electron microscopy:ControlsPregnant ratsAfter 4 weekly injections of 0.1 mg. estradiol benzoate.After 8 daily injections of 150 mcgm. melatonin (pineal hormone).After 8 daily injections of 3 mg. serotonin (melatonin precursor).No ultrastructural differences were evident between the control, and the pregnancy and melatonin groups. However, the estradiol injected animals exhibited a marked increase in the amount and size of rough endoplasmic reticulum within the pineal cells.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Endoplasmic Reticulum-Localized Amyloid beta-Peptide is Degraded in the Cytosol by Two Distinct Degradation Pathways

Traffic ◽  
2004 ◽  
Vol 5 (2) ◽  
pp. 89-101 ◽  
Author(s):  
Anton Schmitz ◽  
Andrea Schneider ◽  
Markus P. Kummer ◽  
Volker Herzog
Keyword(s):  
Endoplasmic Reticulum ◽  
Amyloid Beta ◽  
Amyloid Beta Peptide ◽  
Degradation Pathways ◽  
Beta Peptide

Abstract 269: 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) Decreases Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) and Attenuates Endoplasmic Reticulum Stress in Rat Placental Villi Explants

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Christopher T Banek ◽  
Haley E Gillham ◽  
Sarah M Johnson ◽  
Hans C Dreyer ◽  
Jeffrey S Gilbert
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
De Novo ◽  
Vegf Receptor ◽  
Sprague Dawley ◽  
Hypoxic Conditions ◽  
Ampk Phosphorylation ◽  
Angiogenic Balance ◽  
Placental Villi ◽  
Placental Ischemia

Preeclampsia, defined by the onset of de novo hypertension and proteinuria near the 20th week of gestation, is a major contributor to maternal and fetal morbidity and mortality worldwide. Preeclampsia is often preceded by placental ischemia and an imbalance in circulating angiogenic factors (e.g. VEGF - vascular endothelial growth factor, sFlt-1 - soluble VEGF receptor 1). Recent studies also report increased expression of endoplasmic reticulum (ER) stress products in preeclamptic placentas. Our laboratory recently reported 5-aminoimidazole-4-carboxamide-3-ribonuceloside (AICAR) reduces blood pressure and improves angiogenic balance (increased VEGF, decreased sFlt-1) in rats with placental ischemia-induced hypertension, but the mechanism is unclear. We hypothesized AICAR would decrease sFlt-1, increase AMPK phosphorylation, and decrease ER stress in hypoxic placental villous explants. On day 19 of pregnancy, placentas were isolated from four Sprague-Dawley rats and immediately dissected in ice-cold phosphate-buffered saline. Explants were cultured for 12 hours in physiologic normoxic (8% O2) and hypoxic (1.5% O2) conditions. All experiments were performed in triplicate. VEGF secretion was unaffected by AICAR treatment in both normoxic and hypoxic conditions. AICAR decreased sFlt -1 secretion in hypoxic villi (2147±116 vs. *1411±67, P<0.05). Additionally, AMPK activation ratio was increased with AICAR, and was hypoxic-dependent (8%: 2.9±0.3; 8%+A: 3.3±0.1; 1.5%: 3.5±0.1; 1.5%+A: *4.5±0.01;*P<.05). Moreover, markers of ER stress were increased with hypoxia, and decreased with AICAR treatment (BiP 8%: 1.2±0.2; 8%+A: 1.0±0.0; 1.5%: *8.3±0.7; 1.5%+A: 1.9±0.0.3;*P<.05), (CHOP 8%: 0.5±0.0; 8%+A: 0.3±0.1; 1.5%: *1.7±0.1; 1.5%+A: 0.7±0.1;*P<.05). ATF4 was not changed with hypoxia or AICAR treatment. The present data show that AICAR stimulates AMPK phosphorylation and decreases ER stress response proteins in hypoxic placental villi. Further, the present data support the hypothesis that AICAR restores angiogenic balance by decreasing sFlt-1 rather than increasing VEGF secretion from placental villi. These findings suggest AICAR may improve placental function during pregnancies complicated by placental-ischemia.

scholarly journals De novo translation initiation on membrane-bound ribosomes as a mechanism for localization of cytosolic protein mRNAs to the endoplasmic reticulum

RNA ◽  
2014 ◽  
Vol 20 (10) ◽  
pp. 1489-1498 ◽  
Author(s):  
Sujatha Jagannathan ◽  
David W. Reid ◽  
Amanda H. Cox ◽  
Christopher V. Nicchitta
Keyword(s):  
Endoplasmic Reticulum ◽  
Translation Initiation ◽  
De Novo ◽  
Cytosolic Protein ◽  
Membrane Bound

scholarly journals The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

2020 ◽  
Author(s):  
Julie Jacquemyn ◽  
Joyce Foroozandeh ◽  
Katlijn Vints ◽  
Jef Swerts ◽  
Patrik Verstreken ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nuclear Envelope ◽  
Nuclear Pore Complex ◽  
Lipid Droplets ◽  
Nuclear Pore ◽  
List Type ◽  
Unknown Mechanism ◽  
Structure Lipid ◽  
Cellular Events ◽  
Upstream Regulator

AbstractTorsin ATPases of the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen inhibit Lipin-mediated phosphatidate (PA) to diacylglycerol (DAG) conversion by an unknown mechanism. This excess PA metabolism is implicated in TOR1A/TorsinA diseases, but it is unclear whether it explains why Torsin concomitantly affects nuclear structure, lipid droplets (LD), organelle and cell growth. Here a fly miniscreen identified that Torsins affect these events via the NEP1R1-CTDNEP1 phosphatase complex. Further, Torsin homo-oligomerization rather than ATPase activity was key to function. NEP1R1-CTDNEP1 activates Lipin by dephosphorylation. We show that Torsin prevents CTDNEP1 from accumulating in the NE and excludes Lipin from the nucleus. Moreover, this repression of nuclear PA metabolism is required for interphase nuclear pore biogenesis. We conclude that Torsin is an upstream regulator of the NEP1R1-CTDNEP1/ Lipin pathway. This connects the ER/NE lumen with PA metabolism, and affects numerous cellular events including it has a previously unrecognized role in nuclear pore biogenesis.HighlightsNuclear envelope PA-DAG-TAG synthesis is independently regulated by Torsin and Torip/LAP1Torsin removes CTDNEP1 from the nuclear envelope and excludes Lipin from the nucleusExcess nuclear envelope NEP1R1-CTDNEP1/ Lipin activity impairs multiple aspects of NPC biogenesisNEP1R1-CTDNEP1/ Lipin inhibition prevents cellular defects associated with TOR1A and TOR1AIP1 / LAP1 disease

scholarly journals Retrograde trafficking of Argonaute 2 acts as a rate-limiting step for de novo miRNP formation on endoplasmic reticulum–attached polysomes in mammalian cells

2020 ◽  
Vol 3 (2) ◽  
pp. e201800161 ◽  
Author(s):  
Mainak Bose ◽  
Susanta Chatterjee ◽  
Yogaditya Chakrabarty ◽  
Bahnisikha Barman ◽  
Suvendra N Bhattacharyya
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
De Novo ◽  
Mirna Biogenesis ◽  
Argonaute 2 ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Cellular Context ◽  
Subcellular Compartmentalization ◽  
Rate Limiting

microRNAs are short regulatory RNAs in metazoan cells. Regulation of miRNA activity and abundance is evident in human cells where availability of target messages can influence miRNA biogenesis by augmenting the Dicer1-dependent processing of precursors to mature microRNAs. Requirement of subcellular compartmentalization of Ago2, the key component of miRNA repression machineries, for the controlled biogenesis of miRNPs is reported here. The process predominantly happens on the polysomes attached with the endoplasmic reticulum for which the subcellular Ago2 trafficking is found to be essential. Mitochondrial tethering of endoplasmic reticulum and its interaction with endosomes controls Ago2 availability. In cells with depolarized mitochondria, miRNA biogenesis gets impaired, which results in lowering of de novo–formed mature miRNA levels and accumulation of miRNA-free Ago2 on endosomes that fails to interact with Dicer1 and to traffic back to endoplasmic reticulum for de novo miRNA loading. Thus, mitochondria by sensing the cellular context regulates Ago2 trafficking at the subcellular level, which acts as a rate-limiting step in miRNA biogenesis process in mammalian cells.

Sign in / Sign up

Export Citation Format

Share Document