Stress management at the ER: Regulators of ER stress-induced apoptosis (original) (raw)

Mediators of endoplasmic reticulum stress-induced apoptosis

Embo Reports, 2006

The efficient functioning of the endoplasmic reticulum (ER) is essential for most cellular activities and survival. Conditions that interfere with ER function lead to the accumulation and aggregation of unfolded proteins. ER transmembrane receptors detect the onset of ER stress and initiate the unfolded protein response (UPR) to restore normal ER function. If the stress is prolonged, or the adaptive

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

International Journal of Molecular Sciences

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 bet...

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

Abstract Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function generating ER stress. ER senses stress mainly by three stress sensor pathways, namely protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2a, inositol-requiring enzyme 1a-X-box-binding protein 1 and activating transcription factor 6-CREBH, which induce unfolded protein responses (UPR) after the recognition of stress. Recent studies have demonstrated that ER stress and UPR signaling are involved in cancer, metabolic disorders, inflammatory diseases, osteoporosis and neurodegenerative diseases. However, the precise knowledge regarding involvement of ER stress in different disease processes is still debatable. Here we discuss the possible role of ER stress in various disorders on the basis of existing literature. An attempt has also been made to highlight the present knowledge of this field which may help to elucidate and conjure basic mechanisms and novel insights into disease processes which could assist in devising better future diagnostic and therapeutic strategies.

Unfolded Protein Response Pathways in Neurodegenerative Diseases

The aggregation of disease-specific misfolded proteins resulting in endoplasmic reticulum stress is associated with early pathological events in many neurodegenerative diseases , and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticu-lum stress sensors. All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed as unfolded protein response (UPR). Recently, the focus of research shifted from work on specific proteins as pathogenesis in these neurodegenerative diseases towards a more specific generic pathway known as UPR. ER is a major organelle for protein quality control, and cellular stress disrupts normal functioning of ER. The UPR acts as a protective mechanism during endo-plasmic reticulum stress, but persistent long-term stress triggers UPR-mediated apoptotic pathways ultimately leading to cell death. Here in this review, we will briefly summarize the molecular events of endoplasmic reticulum stress-associated UPR signaling pathways and their potential therapeutic role in neurodegenerative diseases.

Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

Frontiers in cell and developmental biology, 2017

Unfolded stress response (UPR) is a conserved cellular pathway involved in protein quality control to maintain homeostasis under different conditions and disease states characterized by cell stress. Although three general schemes of and genes induced by UPR are rather well-established, open questions remain including the precise role of UPR in human diseases and the interactions between different sensor systems during cell stress signaling. Particularly, the issue how the normally adaptive and pro-survival UPR pathway turns into a deleterious process causing sustained endoplasmic reticulum (ER) stress and cell death requires more studies. UPR is also named a friend with multiple personalities that we need to understand better to fully recognize its role in normal physiology and in disease pathology. UPR interacts with other organelles including mitochondria, and with cell stress signals and degradation pathways such as autophagy and the ubiquitin proteasome system. Here we review cu...

Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death

International Journal of Molecular Sciences

Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca2+ homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.

Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications

The FEBS journal, 2018

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and...

Modulation of Endoplasmic Reticulum Stress: An Opportunity to Prevent Neurodegeneration?

CNS & Neurological Disorders - Drug Targets, 2015

Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-related diseases) have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, accumulating evidence supports a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.