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.

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 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

Effect of pranoprofen on endoplasmic reticulum stress in the primary cultured glial cells

2009 ◽  
Vol 54 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Toru Hosoi ◽  
Miyako Sasaki ◽  
Sachiko Baba ◽  
Koichiro Ozawa
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Glial Cells

Origine et formation de différents types de vacuoles induites par la multiplication d'Alphavirus Sindbis dans divers systemes cellulaires

1979 ◽  
Vol 25 (12) ◽  
pp. 1452-1459 ◽  
Author(s):  
Yves Lombard ◽  
Philippe Poindron ◽  
Aimé Porte
Keyword(s):  
Endoplasmic Reticulum ◽  
Glial Cells ◽  
Chicken Embryo ◽  
Cytoplasmic Membrane ◽  
Dense Material ◽  
Newborn Mice ◽  
Electron Dense Material ◽  
Double Membrane ◽  
Single Membrane ◽  
Chicken Embryo Fibroblasts

Spherule-containing vacuoles and nucleocapsid-bearing vacuoles (cytopathic vacuoles types 1 and 2 respectively of Grimley et al. 1968) induced by Alphavirus Sindbis were studied in brains from newborn mice, chicken embryo fibroblasts, and two lines of tumoral glial cells from muridae. Endoplasmic reticulum (ER) elements and finely granular electron-dense material also seen in contact with nucleocapsids seemed to be involved in the formation of the classical single-membrane spherule-containing vacuoles. A second type of spherule-containing vacuoles were characterized by their double membrane and an amorphous electron-dense content and were probably derived from mitochondria. Nucleocapsid-bearing vacuoles were formed from modified ER elements and seemed to be linked to excessive synthesis of viral material. Such ER alterations were not observed in RG6 cells. In these cells, there were only spherule-containing vacuoles, while nucleocapsids were seen associated with the cytoplasmic membrane only.

P1-096: IRAK-4 KINASE INHIBITION REDUCES PRO-INFLAMMATORY CYTOKINE SECRETION BUT HAS NO EFFECT ON THE UPTAKE OF AMYLOID BETA BY HUMAN GLIAL CELLS

2014 ◽  
Vol 10 ◽  
pp. P337-P337
Author(s):  
Saskia M. van der Vies ◽  
Elise S. van Haastert ◽  
Sandra Mulder ◽  
Henrietta M. Nielsen ◽  
Rob Veerhuis ◽  
...  
Keyword(s):  
Glial Cells ◽  
Amyloid Beta ◽  
Inflammatory Cytokine ◽  
Cytokine Secretion ◽  
Kinase Inhibition

scholarly journals Increased processing of SINE B2 non coding RNAs unveils a novel type of transcriptome de-regulation underlying amyloid beta neuro-pathology

2020 ◽  
Author(s):  
Yubo Cheng ◽  
Babita Gollen ◽  
Luke Saville ◽  
Christopher Isaac ◽  
Jogender Mehla ◽  
...  
Keyword(s):  
Stress Response ◽  
Rna Polymerase Ii ◽  
Amyloid Beta ◽  
Transcriptional Activation ◽  
Rna Processing ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Amyloid Toxicity ◽  
B2 Rna ◽  
Non Coding Rnas

ABSTRACTMore than 97% of the mammalian genome is non-protein coding, and repetitive elements account for more than 50% of noncoding space. However, the functional importance of many non-coding RNAs generated by these elements and their connection with pathologic processes remains elusive. We have previously shown that B2 RNAs, a class of non-coding RNAs that belong to the B2 family of SINE repeats, mediate the transcriptional activation of stress response genes (SRGs) upon application of a stimulus. Notably, B2 RNAs bind RNA Polymerase II (RNA Pol II) and suppress SRG transcription during pro-stimulation state. Upon application of a stimulus, B2 RNAs are processed into fragments and degraded, which in turn releases RNA Pol II from suppression and upregulates SRGs. Here, we demonstrate a novel role for B2 RNAs in transcriptome response to amyloid beta toxicity and pathology in the mouse hippocampus. In healthy hippocampi, activation of SRGs is followed by a transient upregulation of pro-apoptotic factors, such as p53 and miRNA-34c, which target SRGs creating a negative feedback loop that facilitates transition to the pro-stimulation state. Using an integrative RNA genomics approach, we show that in mouse hippocampi of an amyloid precursor protein knock-in mouse model and in an in vitro cell culture model of amyloid beta toxicity, this regulatory loop is dysfunctional due to increased levels of B2 RNA processing, constitutively elevated SRG expression and high p53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in cells, and is upregulated during amyloid toxicity accelerating the processing of SINE RNAs and SRG hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer’s disease (AD). This data attributes a role to SINE RNA processing in a pathological process as well as a new function to Hsf1 that is independent of its transcription factor activity.

scholarly journals Surf4 Promotes Endoplasmic Reticulum Exit of the Lysosomal Prosaposin-Progranulin Complex

2021 ◽  
Author(s):  
S. Devireddy ◽  
S.M. Ferguson
Keyword(s):  
Endoplasmic Reticulum ◽  
Frontotemporal Dementia ◽  
Lysosomal Storage Disease ◽  
Intracellular Trafficking ◽  
Secretory Pathway ◽  
Storage Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage ◽  
Efficient Delivery ◽  
Lysosomal Protein

AbstractProgranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interacts with prosaposin, another lysosomal protein, within the lumen of the endoplasmic reticulum (ER) and that prosaposin is required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates a network of interactions occurring early in the secretory pathway that promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

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