Exploring ER stress response in cellular aging and neuroinflammation in Alzheimer's disease

One evident hallmark of Alzheimer’s disease (AD) is the irregular accumulation of proteins due to changes in proteostasis involving endoplasmic reticulum (ER) stress. To alleviate ER stress and reinstate proteostasis, cells undergo an integrated signaling cascade called the unfolded protein response (UPR) that reduces the number of misfolded proteins and inhibits abnormal protein accumulation. Aging is associated with changes in the expression of ER chaperones and folding enzymes, leading to the impairment of proteostasis, and accumulation of misfolded proteins. The disrupted initiation of UPR prevents the elimination of unfolded proteins, leading to ER stress. In AD, the accumulation of misfolded proteins caused by sustained cellular stress leads to neurodegeneration and neuronal death. Current research has revealed that ER stress can trigger an inflammatory response through diverse transducers of UPR. Although the involvement of a neuroinflammatory component in AD has been documented for decades, whether it is a contributing factor or part of the neurodegenerative events is so far unknown. Besides, a feedback loop occurs between neuroinflammation and ER stress, which is strongly associated with neurodegenerative processes in AD. In this review, we focus on the current research on ER stress and UPR in cellular aging and neuroinflammatory processes, leading to memory impairment and synapse dysfunction in AD.     

ERADicate ER stress or die trying

Stress within the endoplasmic reticulum (ER) induces a sophisticated network of pathways termed the unfolded protein response (UPR), which is mediated through the ER transmembrane sensors PERK, ATF6, and IRE1. The UPR coordinates the temporary downregulation of protein translation, the upregulation of ER chaperones and folding machinery, and the enhanced expression of components necessary for ER-associated degradation (ERAD) essential for decreasing ER stress by clearing terminally misfolded proteins from the ER. Repetitive but futile folding attempts not only prolong ER stress but can also result in reactive oxygen species (ROS) generation, both of which may result in cell death. Additional mechanisms for decreasing stress and the protein load in the ER have been recently revealed. They include a newly identified function of IRE1 in degradation of select secretory protein mRNAs, a "preemptive" quality control responsible for averting translocation of select secretory proteins into the ER, upregulation of forward trafficking to allow misfolded proteins with intact exit signals to exit the ER, and upregulation of autophagy. The saturation or failure of some or all of these mechanisms can result in cell death and disease, including diabetes and a number of late-onset neurologic diseases.     

Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle

Proteins in the endoplasmic reticulum (ER) require an efficient system of molecular chaperones whose role is to assure their proper folding and to prevent accumulation of unfolded proteins. The response of cells to accumulation of unfolded proteins in the ER is termed "unfolded protein response" (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress, resulting from the accumulation of the unfolded/misfolded proteins. Because intracellular inclusions, containing either amyloid-beta (Abeta) or phosphorylated tau, are the characteristic feature of sporadic inclusion body myositis (s-IBM) muscle biopsies, we studied expression and immunolocalization of five ER chaperones, calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72, in s-IBM and control muscle biopsies. Physical interaction of the ER chaperones with amyloid-beta precursor protein (AbetaPP) was studied by a combined immunoprecipitation/immunoblotting technique in s-IBM and control muscle biopsies, and in AbetaPP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, all five of the ER chaperones were immunodetected in the form of inclusions that co-localized with amyloid-beta. By immunoblotting, expression of ER chaperones was greatly increased as compared to the controls. By immunoprecipitation/immunoblotting experiments, ER chaperones co-immunoprecipitated with AbetaPP. Our studies provide evidence of the UPR in s-IBM muscle and demonstrate for the first time that the ER chaperones calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72 physically associate with AbetaPP in s-IBM muscle, suggesting their playing a role in AbetaPP folding and processing.     

X-盒结合蛋白1生物学功能研究进展

研究发现X-盒结合蛋白1(X-box binding protein1,XBP1)与内质网中蛋白质的折叠密切相关,参与调控未折叠蛋白的折叠、修饰、分选与包装;此外,XBP1是联系未折叠蛋白反应元件、脂类生物合成和内质网生物合成的纽带。细胞在异常情况下会诱导内质网压力,导致蛋白质不能折叠或者错误折叠,XBP1作为未折叠蛋白反应元件的转录调控因子,指导蛋白质再折叠和降解,帮助细胞缓解内质网压力。了解与阐明细胞中XBP1的分子生物学作用机制,有利于揭示内质网中蛋白质加工、包装的作用机理。     

The unfolded protein response--a stress signaling pathway of the endoplasmic reticulum

The endoplasmic reticulum (ER) is a factory for folding and maturation of newly synthesized transmembrane and secretory proteins. The ER provides stringent quality control systems to ensure that only correctly folded proteins exit the ER and unfolded or misfolded proteins are retained and ultimately degraded. A number of biochemical and physiological stimuli can change ER homeostasis, impose stress to the ER, and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen. The ER has evolved stress response signaling pathways collectively called the unfolded protein response (UPR) to cope with the accumulation of unfolded or misfolded proteins. This review summarizes our understanding of the UPR signaling developed in the recent years.     

ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology

The endoplasmic reticulum (ER) is involved in several crucial cellular functions, e.g. protein folding and quality control, maintenance of Ca²⁺ balance, and cholesterol synthesis. Many genetic and environmental insults can disturb the function of ER and induce ER stress. ER contains three branches of stress sensors, i.e. IRE1, PERK and ATF6 transducers, which recognize the misfolding of proteins in ER and activate a complex signaling network to generate the unfolded protein response (UPR). Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving misfolding and aggregation of proteins in conjunction with prolonged cellular stress, e.g. in redox regulation and Ca²⁺ homeostasis. Emerging evidence indicates that the UPR is activated in neurons but not in glial cells in AD brains. Neurons display pPERK, peIF2α and pIRE1α immunostaining along with abundant diffuse staining of phosphorylated tau protein. Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers. The most potent pathways are IRE1-TRAF2, PERK-eIF2α, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways. We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.     

Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?

The endoplasmic reticulum (ER) is a well-orchestrated protein-folding machine composed of protein chaperones, proteins that catalyze protein folding, and sensors that detect the presence of misfolded or unfolded proteins. A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting the secretory pathway and ensures that persistently misfolded proteins are directed toward a degradative pathway. The unfolded protein response (UPR) is an intracellular signaling pathway that coordinates ER protein-folding demand with protein-folding capacity and is essential to adapt to homeostatic alterations that cause protein misfolding. These include changes in intraluminal calcium, altered glycosylation, nutrient deprivation, pathogen infection, expression of folding-defective proteins, and changes in redox status. The ER provides a unique oxidizing folding-environment that favors the formation of the disulfide bonds. Accumulating evidence suggests that protein folding and generation of reactive oxygen species (ROS) as a byproduct of protein oxidation in the ER are closely linked events. It has also become apparent that activation of the UPR on exposure to oxidative stress is an adaptive mechanism to preserve cell function and survival. Persistent oxidative stress and protein misfolding initiate apoptotic cascades and are now known to play predominant roles in the pathogenesis of multiple human diseases including diabetes, atherosclerosis, and neurodegenerative diseases.     

内质网应激

内质网应激(ER stress)是真核细胞的一种保护性应激反应,通过ER stress细胞降低胞内未折叠蛋白的浓度,阻碍未折叠蛋白发生凝集,哺乳动物细胞ER stress过程比原生动物和酵母细胞要复杂,但都具有一些共同的特点。     

Mechanisms and models of endoplasmic reticulum stress in chondrodysplasia

Chondrodysplasias are a group of genetic disorders that affect the development and growth of cartilage. These disorders can result in extreme short stature, craniofacial defects, joint malformation, and early osteoarthritis; severely impacting quality of life for affected individuals. Many chondrodysplasias are caused by mutations in genes encoding cartilage extracellular matrix (ECM) proteins. These mutations typically result in synthesis of abnormal proteins that are improperly folded, and hence inappropriately retained within the endoplasmic reticulum (ER) of the cell, activating ER stress and the unfolded protein response (UPR), an adaptive cellular response to minimize production of the mutant protein and/or to enhance protein folding, degradation or export. If prolonged, activation of the UPR causes apoptotic cell death. Many human disorders have an underlying mechanism in UPR activation, and targeting ER stress pathways is showing promise for development of therapeutics for these conditions. Understanding and modeling the UPR in chondrodysplasia will be essential to advance such targeted approaches for the benefit of chondrodysplasia patients. The focus of this review is to compare the mechanistic sequelae of ECM protein mutations in chondrodysplasia that may cause chondrocyte ER stress and UPR activation, and to present current and future directions in chondrodysplasia disease modeling and therapeutic intervention. Developmental Dynamics 243:875–893, 2014. © 2014 Wiley Periodicals, Inc.     

The Unfolded Protein Response in Homeostasis and Modulation of Mammalian Immune Cells

The endoplasmic reticulum (ER) plays important roles in eukaryotic protein folding and lipid biosynthesis. Several exogenous and endogenous cellular sources of stress can perturb ER homeostasis leading to the accumulation of unfolded proteins in the lumen. Unfolded protein accumulation triggers a signal-transduction cascade known as the unfolded protein response (UPR), an adaptive mechanism which aims to protect cells from protein aggregates and to restore ER functions. Further to this protective mechanism, in immune cells, UPR molecular effectors have been shown to participate in a wide range of biological processes such as cell differentiation, survival and immunoglobulin and cytokine production. Recent findings also highlight the involvement of the UPR machinery in the maturational program and antigen presentation capacities of dendritic cells. UPR is therefore a key element in immune system homeostasis with direct implications on both adaptive and innate immune responses. The present review summarizes the knowledge on the emerging roles of UPR signaling cascades in mammalian immune cells as well as the consequences of their dysregulation in relation to the pathogenesis of several diseases.     

Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol

Increasing evidence indicates that endoplasmic reticulum (ER) stress is involved in various diseases. In the human heart, ischemia/reperfusion has been correlated to ER stress, and several markers of the unfolded protein response (UPR) participate during cardiac remodeling and fibrosis. Here, we used isoproterenol (ISO) injection as a model for in vivo cardiac fibrosis. ISO induced significant cardiomyocyte loss and collagen deposition in the damaged areas of the endocardium. These responses were accompanied by an increase in the protein levels of the luminal ER chaperones BIP and PDI, as well as an increase in the UPR effector CHOP. The use of the chemical chaperone 4-phenylbutyric acid (4-PBA) prevented the activation of the UPR, the increase in luminal chaperones and also, leads to decreased collagen deposition, cardiomyocyte loss into the damaged zones. Our results suggest that cardiac damage and fibrosis induced in vivo by the beta-adrenergic agonist ISO are tightly related to ER stress signaling pathways, and that increasing the ER luminal folding capacity with exogenously administrated 4-PBA is a powerful strategy for preventing the development of cardiac fibrosis. Additionally, 4-PBA might prevent the loss of cardiomyocytes. Our data suggests that the attenuation of ER stress pathways with pharmacological compounds such as the chemical chaperone 4-PBA can prevent the development of cardiac fibrosis and adverse remodeling.     

内质网应激介导神经变性疾病错折叠蛋白的神经毒性

神经变性疾病(neurodegenerative diseases,NDD)的共同病变基础是细胞内的蛋白处理机制失效而出现错折叠蛋白的集聚并产生神经毒性[1].环境毒素作用、氧化损伤、线粒体功能失常、胞内Ca2 失衡等因素均可能与NDD的发病有关[2].但面对错折叠蛋白,细胞必然通过内质网启动未折叠蛋白反应(unfolded protein response,UPR),这就提示我们内质网应激(endoplasmic reticulum stress,ERstress)可能在NDD发病过程中起关键作用.近期研究表明,内质网应激广泛存在于各种NDD中,并介导错折叠蛋白产生神经毒性及细胞凋亡作用.这里我们主要对内质网应激在发病率最高的3种NDD中所起的作用加以阐述,以期为未来NDD的研究及治疗提供切实可行的思路.