scholarly journals Human tauopathies are not associated with an activated unfolded protein response

2019 ◽  
Author(s):  
A. P. Pitera ◽  
I. J. Hartnell ◽  
D. Boche ◽  
V. O’Connor ◽  
K. Deinhardt
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Progressive Supranuclear Palsy ◽  
Unfolded Protein Response ◽  
Tau Protein ◽  
Human Tissue ◽  
Protein Quality ◽  
Protein Tau ◽  
Unfolded Protein ◽  
Protein Response

AbstractTauopathies are the neurodegenerative diseases associated with the accumulation of misfolded tau protein. Despite many years of investigation, the mechanisms underpinning tau dependent proteinopathy remains to be elucidated. A protein quality control pathway within the endoplasmic reticulum (ER), called unfolded protein response (UPR), has been suggested as a possible response implicated in the misfolded tau-mediated neurodegeneration. However, the question arose: how does the cytosolic protein tau that does not enter the ER induce a response stemming from this compartment? In this study we investigated three different human tauopathies to establish whether these diseases are associated with the activation of UPR. We probed for the modulation of several reliable UPR markers in mRNA and proteins extracted from 20 brain samples from Alzheimer’s disease (AD) patients, 11 from Pick’s disease (PiD) and 10 from Progressive Supranuclear Palsy (PSP) patients coupled to equal numbers of age-matched non-demented controls. This showed that different markers of UPR are not changed in any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. These data from human tissue further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased associated activation of UPR.

scholarly journals Proteostasis In The Endoplasmic Reticulum: Road to Cure

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1793 ◽  
Author(s):  
Nam ◽  
Jeon
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Quality ◽  
Tumor Development ◽  
Therapeutic Interventions ◽  
Secretory Proteins ◽  
Unfolded Protein ◽  
Stress Signals ◽  
Protein Response

The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER–mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment.

scholarly journals Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

2004 ◽  
Vol 15 (6) ◽  
pp. 2537-2548 ◽  
Author(s):  
Satomi Nadanaka ◽  
Hiderou Yoshida ◽  
Fumi Kano ◽  
Masayuki Murata ◽  
Kazutoshi Mori
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control System ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

Age and dose-dependent effects of alpha-lipoic acid on human microtubule-associated protein tau-induced endoplasmic reticulum unfolded protein response: implications for Alzheimer’s disease

2020 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Nima Sanadgol ◽  
Kazem Parivar ◽  
Gholamhassan Vaezi
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Lipoic Acid ◽  
Alpha Lipoic Acid ◽  
Protein Patterns ◽  
Locomotor Function ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Unfolded Protein ◽  
Protein Response

AbstractBackgroundIn human tauopathies, pathological aggregation of misfolded/unfolded proteins particularly microtubule-associated protein tau (MAPT, tau) is considered to be essential mechanisms that trigger the induction of endoplasmic reticulum (ER) stress. Here we assessed the molecular effects of natural antioxidant alpha-lipoic acid (ALA) in human tauR406W (htau)-induced ER unfolded protein response (ERUPR) in the young and older flies.MethodsIn order to reduce htau neurotoxicity during brain development, we used a transgenic model of tauopathy where the maximum toxicity was observed in adult flies. Then, the effects of ALA (0.001, 0.005, and 0.025% w/w of diet) in htau-induced ERUPR in the ages 20 and 30 days were evaluated.ResultsData from expression (mRNA and protein) patterns of htau, analysis of eyes external morphology as well as larvae olfactory memory were confirmed our tauopathy model. Moreover, expression of ERUPR-related proteins involving activating transcription factor 6 (ATF6), inositol regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) were upregulated and locomotor function decreased in both ages of the model flies. Remarkably, the lower dose of ALA modified ERUPR and supported the reduction of behavioral deficits in youngest adults through enhancement of GRP87/Bip, reduction of ATF6, downregulation of PERK-ATF4 pathway, and activation of the IRE1-XBP1 pathway. On the other hand, only a higher dose of ALA was able to affect the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA exerts their higher protective effects on the locomotor function of younger adults when htauR406W expressed in all neurons (htau-elav) and mushroom body neurons (htau-ok), we proposed that ALA has age-dependent effects in this model.ConclusionTaken together, based on our results we conclude that aging potentially influences the ALA effective dose and mechanism of action on tau-induced ERUPR. Further molecular studies will warrant possible therapeutic applications of ALA in age-related tauopathies.

scholarly journals Unfolded Protein Response of the Endoplasmic Reticulum in Tumor Progression and Immunogenicity

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Yoon Seon Yoo ◽  
Hye Gyeong Han ◽  
Young Joo Jeon
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Tumor Progression ◽  
Unfolded Protein Response ◽  
Therapeutic Intervention ◽  
Transmembrane Proteins ◽  
Eukaryotic Cells ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
Protein Response

The endoplasmic reticulum (ER) is a pivotal regulator of folding, quality control, trafficking, and targeting of secreted and transmembrane proteins, and accordingly, eukaryotic cells have evolved specialized machinery to ensure that the ER enables these proteins to acquire adequate folding and maturation in the presence of intrinsic and extrinsic insults. This adaptive capacity of the ER to intrinsic and extrinsic perturbations is important for maintaining protein homeostasis, which is termed proteostasis. Failure in adaptation to these perturbations leads to accumulation of misfolded or unassembled proteins in the ER, which is termed ER stress, resulting in the activation of unfolded protein response (UPR) of the ER and the execution of ER-associated degradation (ERAD) to restore homeostasis. Furthermore, both of the two axes play key roles in the control of tumor progression, inflammation, immunity, and aging. Therefore, understanding UPR of the ER and subsequent ERAD will provide new insights into the pathogenesis of many human diseases and contribute to therapeutic intervention in these diseases.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
Yasuyuki Nomura
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.

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