Endoplasmic reticulum enrollment in Alzheimer’s disease
ABSTRACT Alzheimer's disease (AD) poses a huge challenge for society and health care worldwide as molecular pathogenesis of the disease is poorly understood and curative treatment does not exist. The mechanisms leading to accelerated neuronal cell death in AD are still largely unknown, but accumulation of misfolded disease-specific proteins has been identified as potentially involved. In the present review, we describe the essential role of endoplasmic reticulum (ER) in AD. Despite the function that mitochondria may play as the central major player in the apoptotic process, accumulating evidence highlights ER as a critical organelle in AD. Stress that impairs ER physiology leads to accumulation of unfolded or misfolded proteins, such as amyloid β (Aβ) peptide, the major component of amyloid plaques. In an attempt to ameliorate the accumulation of unfolded proteins, ER stress triggers a protective cellular mechanism, which includes the unfolded protein response (UPR). However, when activation of the UPR is severe or prolonged enough, the final cellular outcome is pathologic apoptotic cell death. Distinct pathways can be activated in this process, involving stress sensors such as the JNK pathway or ER chaperones such as Bip/GRP94, stress modulators such as Bcl-2 family proteins, or even stress effectors such as caspase-12. Here, we detail the involvement of the ER and associated stress pathways in AD and discuss potential therapeutic strategies targeting ER stress.
- SourceAvailable from: Dwaipayan Sen
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- "Various stresses to the ER such as accumulation of unfolded/misfolded/mutated proteins (Hetz 2012, Viana et al. 2012), disturbances in redox status and endogenous reactive oxygen species (ROS) production (Fedoroff 2006), hypoxia (Sawada et al. 2008), hyperglycemia , and hyperlipidemia (Fonseca et al. 2011, Back et al. 2012), disturbances in calcium regulation (Gorlach et al. 2006) and viral infections (Zhang and Wang 2012, Sen et al. 2014) disrupt the ER homeostasis and make it dysfunctional. Under these conditions the ER is said to be under " stress " . "
ABSTRACT: Parkinson’s disease is the second most common neurodegenerative disease which affects almost 1% of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson’s disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson’s disease leading to neurodegeneration.Acta neurobiologiae experimentalis 04/2015; 75:1-26. · 2.24 Impact Factor
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- "However, what is the causal relationship between ER and autophagy in AD? ER stress is a potent inducer of autophagy, namely macroautophagy (Hoyer-Hansen and Jaattela, 2007), as depicted in b F1 Figure 1. Accumulating evidence shows that UPR ER activation is an early event in AD (Pereira, 2013; Viana et al., 2012). As a matter of fact, UPR ER activation markers have been extensively documented in postmortem brain tissue from AD subjects and in animal and in vitro models of the disease (Hoozemans et al., 2009, 2012). "
ABSTRACT: Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.DNA and Cell Biology 02/2015; 34(4). DOI:10.1089/dna.2014.2757 · 1.99 Impact Factor
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- "Accumulation of unfolded/misfolded/mutated proteins (Hetz and Soto, 2006; Viana et al., 2012), disturbances in cellular redox regulation and endogenous reactive oxygen species (ROS) production (Fedoroff, 2006), hypoxia (Feldman et al., 2005; Sawada et al., 2008), hyperglycemia, and hyperlipidemia (Fonseca et al., 2011; Abbreviations: ADNF, activity-dependent neurotrophic factor; AIP1, ASK1-interacting protein-1; ALS, amyotrophic lateral sclerosis; AMPA, α- amino-3-hydroxy-5-methylisoxazole-4-propionate acid; AP-1, activator protein-1; APR, acute phase response; ARD, ankyrin repeat domain; ASK1, apoptosis signal-regulating kinase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATP, adenosine 5-triphosphate; Bad, Bcl-2-associated death promoter; BAFF, B cell activating factor; BAPTA-AM, 1,2-Bis(2- aminophenoxy)ethane-N,N,N ,N -tetraacetic acid tetrakis(acetoxymethyl)ester; Bcl2, B-cell lymphoma 2; Bcl xl, B-cell lymphoma-extra large; BHA, butylated hydroxyanisole; Bim, B-cell lymphoma 2 interacting mediator of cell death; BIP, immunoglobulin heavy chain binding protein; CDDO, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; CDDO Me, methyl 2-cyano-3,12- dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl; CEMB, cyano enone of methyl boswellates; CHOP, CCAAT/enhancer-binding protein homologous protein; CNX, Calnexin; CREB, cAMP response-element-binding; CRP, C-reactive protein; CRT, Calreticulin; DTT, dithiothreitol; EDEM, ER degradation-enhancing α-mannosidase-like protein; eIF2α, eukaryotic translation initiation factor; ER, endoplasmic reticulum; ERAD, ER-associated degradation; ERKs, extracellular signal-regulated kinases; ERO, ER membrane associated oxidoreductin; ERSE, ER stress response element; ERQC, Endoplasmic reticulum quality control system; FAD, Flavin adenine dinucleotide; FoxO1, fork head box O1; GLS, Golgi-localization signal; GRP, glucose-regulated protein; GSH, glutathione; GSSH, glutathione to oxidized glutathione; IBD, inflammatory bowel disease; IEC, intestinal epithelial cells; IKK, IκB kinase; IAPs, inhibitor of apoptotic proteins; IL-1R, interleukin 1-receptor; InsP3, inositol 1,4,5-triphosphate RyRs, ryanodine receptors; Back et al., 2012), aberrations in calcium regulation (Gorlach et al., 2006), viral infections (He, 2006; Zhang and Wang, 2012) act as stress signals and alter ER homeostasis making it dysfunctional. In response to such diverse signals, ER elicits a protective or adaptive response called unfolded-protein response (UPR) with an aim to restore ER homeostasis; however, if the stress signal is severe and/or prolonged, ER triggers cell death pathways (Szegezdi et al., 2006; Kim et al., 2008a; Cheng and Yang, 2011; Benbrook and Long, 2012). "
ABSTRACT: Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.Frontiers in Cellular Neuroscience 07/2014; 8:213. DOI:10.3389/fncel.2014.00213 · 4.18 Impact Factor