Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

2009 ◽  
Vol 118 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Toru Hosoi ◽  
Koichiro Ozawa
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Unfolded Protein ◽  
Pathological Conditions ◽  
Disease Mechanisms ◽  
Obesity And Diabetes ◽  
Protein Response

Various stresses, which impair ER (endoplasmic reticulum) function, lead to an accumulation of unfolded or misfolded proteins. ER stress triggers many rescuer responses, including a UPR (unfolded protein response). Increasing evidence has suggested that ER stress is involved in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and cerebral ischaemic insults), cancer, obesity and diabetes. In the present review, we consider the importance of ER stress under pathological conditions in mammals. Furthermore, we discuss the therapeutic potential for treatment targeting ER stress.

scholarly journals ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Felipe Cabral-Miranda ◽  
Claudio Hetz
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Major Element ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Unfolded Protein ◽  
Disease Mechanisms ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

scholarly journals Inadequate BiP availability defines endoplasmic reticulum stress

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Milena Vitale ◽  
Anush Bakunts ◽  
Andrea Orsi ◽  
Federica Lari ◽  
Laura Tadè ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Heavy Chain ◽  
Target Gene ◽  
Immunoglobulin M ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Secretory Immunoglobulin

How endoplasmic reticulum (ER) stress leads to cytotoxicity is ill-defined. Previously we showed that HeLa cells readjust homeostasis upon proteostatically driven ER stress, triggered by inducible bulk expression of secretory immunoglobulin M heavy chain (μs) thanks to the unfolded protein response (UPR; Bakunts et al., 2017). Here we show that conditions that prevent that an excess of the ER resident chaperone (and UPR target gene) BiP over µs is restored lead to µs-driven proteotoxicity, i.e. abrogation of HRD1-mediated ER-associated degradation (ERAD), or of the UPR, in particular the ATF6α branch. Such conditions are tolerated instead upon removal of the BiP-sequestering first constant domain (CH1) from µs. Thus, our data define proteostatic ER stress to be a specific consequence of inadequate BiP availability, which both the UPR and ERAD redeem.

3-O-Hydroxytyrosol glucuronide and 4-O-hydroxytyrosol glucuronide reduce endoplasmic reticulum stress in vitro

2015 ◽  
Vol 6 (10) ◽  
pp. 3275-3281 ◽  
Author(s):  
Elena Giordano ◽  
Olivier Dangles ◽  
Njara Rakotomanomana ◽  
Silvia Baracchini ◽  
Francesco Visioli
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Atherosclerosis Development ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress is important for atherosclerosis development and is mediated by the unfolded protein response (UPR).

scholarly journals Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Keigo Tanaka ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Brain Function ◽  
Review Article ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractIncreasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.

scholarly journals Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jennifer L Mamrosh ◽  
Jae Man Lee ◽  
Martin Wagner ◽  
Peter J Stambrook ◽  
Richard J Whitby ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Nuclear Receptor ◽  
Stress Resistance ◽  
Unfolded Protein ◽  
Human Disorders ◽  
Protein Response

Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress.

scholarly journals Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Sagir Mustapha ◽  
Mustapha Mohammed ◽  
Ahmad Khusairi Azemi ◽  
Ismaeel Yunusa ◽  
Aishatu Shehu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Protein ◽  
Metabolic Functions ◽  
Chronic Hyperglycemia ◽  
Obesity And Diabetes ◽  
Activating Transcription Factor ◽  
Protein Response

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.

scholarly journals Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Adrien Le Thomas ◽  
Elena Ferri ◽  
Scot Marsters ◽  
Jonathan M. Harnoss ◽  
David A. Lawrence ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Stem Loop ◽  
Unfolded Protein ◽  
Cellular Mrnas ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractInositol requiring enzyme 1 (IRE1) mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.

scholarly journals Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

2020 ◽  
Vol 21 (17) ◽  
pp. 6127 ◽  
Author(s):  
Rose Ghemrawi ◽  
Mostafa Khair
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Unfolding ◽  
Protein Quality ◽  
Unfolded Protein ◽  
Treatment And Prevention ◽  
Protein Response

The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.

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