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.     

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.     

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.     

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.     

Expanding insights on the involvement of endoplasmic reticulum stress in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood. Environmental factors, oxidative damage, misfolded protein aggregates, ubiquitin-proteasome system impairment, and mitochondrial dysfunction might all be involved. Recent studies point to activation of endoplasmic reticulum (ER) stress-mediated cell death linked to PD. Accumulation of unfolded and/or misfolded proteins in the ER lumen induces ER stress. To withstand such potentially lethal conditions, intracellular signaling pathways collectively termed the unfolded protein responses (UPR) are activated. The UPR include translational attenuation, induction of ER resident chaperones, and degradation of misfolded proteins through the ER-associated degradation. In case of severe and/or prolonged ER stress, cellular signals leading to cell death are activated. Accumulating evidence suggests that ER stress induced by aberrant protein degradation is implicated in PD. Here the authors review the emerging role of ER stress in PD and related disorders, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to provide novel avenues to potential therapies.     

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。     

Endoplasmic reticulum stress in autoimmune diseases: Can altered protein quality control and/or unfolded protein response contribute to autoimmunity? A critical review on Sjögren's syndrome

For many years, researchers in the field of autoimmunity have focused on the role of the immune components in the etiopathogenesis of autoimmune diseases. However, some studies have demonstrated the importance of target tissues in their pathogenesis and the breach of immune tolerance. The immune system as well as target tissue cells (plasmatic, β-pancreatic, fibroblast-like synoviocytes, thyroid follicular and epithelial cells of the lachrymal glands, salivary glands, intestine, bronchioles and renal tubules) share the characteristic of secretory cells with an extended endoplasmic reticulum (ER). The function of these cells depends considerably on a normal ER function and calcium homeostasis, so they can produce and secrete their main components, which include glycoproteins involved in antigenic presentation such as major histocompatibility complex (MHC) class I and II. All these proteins are synthesized and modified in the ER, and for this reason disturbances in the normal functions of this organelle such as protein folding, protein quality control, calcium homeostasis and redox balance, promote accumulation of unfolded or misfolded proteins, a condition known as ER stress. Autoimmune diseases are characterized by inflammation, which has been associated with an ER stress condition. Interestingly, patients with these diseases contain circulating auto-antibodies against chaperone proteins (such as Calnexin and GRP94), thus affecting the folding and assembly of MHC class I and II glycoproteins and their loading with peptide.The main purpose of this article is to review the involvement of the protein quality control and unfolded protein response (UPR) in the ER protein homeostasis (proteostasis) and their alterations in autoimmune diseases. In addition, we describe the interaction between ER stress and inflammation and evidences are shown of how autoimmune diseases are associated with an ER stress condition, with a special emphasis on the second most prevalent autoimmune rheumatic disease, Sjögren's syndrome.     

Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders

Protein quality control is a critical feature of intracellular homeostasis. In particular, unfolded or misfolded proteins resulting from environmental stresses or free radicals are rapidly degraded via the ubiquitin-proteasome pathway. Nitric oxide (NO), a free radical gas, has been reported to be involved in such processes as vasorelaxation and neurotransmission. Conversely, NO also is implicated in neuronal cell death or neurodegeneration. Recent reports suggest that S-nitrosylation of proteins is a significant cause of neural dysfunction leading to neurodegenerative disorders. Specifically, S-nitrosylation of parkin eventually leads to the accumulation of unfolded proteins and subsequent neuronal death. The focus of this review is the identity of the target of NO. Nitrosative stress prevents normal functioning of the endoplasmic reticulum (ER) via S-nitrosylation of protein-disulfide isomerase (PDI), which is located in the ER lumen. This may contribute to the accumulation of misfolded proteins, as well as sustained activation of the unfolded protein response (UPR) pathway. These phenomena may be linked to the development of sporadic neurodegenerative diseases.     

Role of endoplasmic reticulum stress and protein misfolding in disorders of the liver and pancreas

The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. The fraction of protein passing through the ER represents a large proportion of the total protein in the cell. Protein folding, glycosylation, sorting and transport are essential tasks of the ER and a compromised ER folding network has been recognized to be a key component in the disease pathogenicity of common neurodegenerative, metabolic and malignant diseases. On the other hand, the ER protein folding machinery also holds significant potential for therapeutic interventions. Many causes can lead to ER stress. A disturbed calcium homeostasis, the generation of reactive oxygen species (ROS) and a persistent overload of misfolded proteins within the ER can drive the course of adisease. In this review the role of ER-stress in diseases of the liver and pancreas will be examined using pancreatitis and Wilson´s disease as examples. Potential therapeutic targets in ER-stress pathways will also be discussed.     

How transmembrane proteins sense endoplasmic reticulum stress

The unfolded protein response (UPR) is an adaptive stress response in which cells recover from the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) by increasing its protein-folding capacity. The IRE1 pathway in the UPR is evolutionarily conserved from yeast to human, and two other pathways involving PERK and ATF6 have also evolved in higher eukaryotes. These three intracellular signaling pathways originate in the ER lumen, where unfolded or misfolded proteins are recognized by the three transmembrane ER stress sensors IRE1, PERK, and ATF6. This review focuses on current progress with efforts to elucidate how stress sensors recognize the accumulation of unfolded proteins.     

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.     

The functional role of stress proteins in ER stress mediated cell death

The endoplasmic reticulum (ER) is an intracellular organelle involved in biosynthesis and the secretory pathway. This organelle has many resident proteins including biosynthetic enzymes and secretory proteins. Recent studies have suggested that dysfunction of the ER or secretory pathway is involved in the pathogenesis of various human diseases. Some stresses acting on the ER, which are designated ER stress, induce the accumulation of unfolded/misfolded proteins in the ER, leading to cell death. Misfolded proteins are retained until they form their native conformation or returned to the cytosol for degradation by the proteasome. Among the ER-resident proteins, molecular chaperones prevent aggregation of proteins within the ER, and orchestrate the ER quality control systems. We have reported the roles of novel stress proteins, namely 150-kDa oxygen-regulated protein, 94-kDa glucose-regulated protein and RA410. These proteins are induced significantly by hypoxia or oxidative stress and have cytoprotective effects under these conditions. These findings suggest that hypoxia and oxidative stress target the ER and secretory pathway, resulting in ER stress, and that these proteins exert cytoprotective effects in various diseases associated with ER stress.     

ER and aging—Protein folding and the ER stress response

The endoplasmic reticulum (ER) is a multifunctional organelle which co-ordinates protein folding, lipid biosynthesis, calcium storage and release. Perturbations that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up-regulation of a signaling pathway called the ER stress response or the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. Age-related declines and activity in key molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. This review will highlight age-related changes in the protein folding machinery and in the UPR.     

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.     

Alterations of Hrd1 expression in various encephalic regional neurons in 6-OHDA model of Parkinson's disease

The ubiquitin-proteasome system plays a central role in regulated degradation of cellular proteins under different physiological conditions. Accumulation of misfolded proteins is involved in the pathogenesis of many neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD). Hrd1 is a newly identified ubiquitin ligase involved in degradation of misfolded proteins from the endoplasmic reticulum (ER), thereby protecting cells against ER stress. Increasing evidence has linked ER stress to PD pathogenesis. However, the expression of Hrd1 in PD brain remains elusive. In the present study, the expression of Hrd1 in different encephalic regions was studied in 6-OHDA model of Parkinson's disease by immunohistochemistry. The results showed that Hrd1 was up-regulated in 6-OHDA-treated mice in various encephalic regional neurons, especially those in hippocampus, substantia nigra (SN), subthalamic nucleus (STN), striatum and frontal lobe. It suggested that Hrd1 up-regulation may represent a protective response against neurodegeneration in PD.     

内质网应激在动脉粥样硬化发生、发展和防治中的作用

Endoplasmic reticulum (ER) is a multifunctional organelle responsible for the synthesis and folding of proteins and regulation of calcium homeostasis. Multiple stimuli, such as oxidative stress, glycosylation change and so on, lead to ER dysfunction characterized by the accumulation of unfolded and/or misfolded proteins and calcium homeostasis imbalance (ER stress). Mode-rate ER stress is an important cytoprotective mechanism against stressors. However, severe and/or prolonged ER stress can trigger apoptotic signaling including CHOP, caspase-12 and JNK pathways. Recent studies have shown that ER stress plays a critical role in the development of atherosclerosis and it can bring about inhibitory effects on the progression of atherosclerosis through the intervention of the relevant pathways, which may be a new therapeutic target for atherosclerosis.