Converging Pathways in the Occurrence of Endoplasmic Reticulum (ER) Stress in Huntingtons Disease

Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile.
Current Molecular Medicine (Impact Factor: 3.62). 02/2011; 11(1):1-12. DOI: 10.2174/156652411794474419
Source: PubMed


A variety of neurological diseases including Huntington's disease (HD), Alzheimer's disease and Parkinson's disease share common neuropathology, primarily featuring the presence of abnormal protein inclusions containing specific misfolded proteins. Mutations leading to expansion of a poly-glutamine track in Huntingtin cause HD, and trigger its misfolding and aggregation. Recent evidence indicates that alterations in the secretory pathway, in particular the endoplasmic reticulum (ER), are emerging features of HD. Although it is not clear how cytoplasmic/nuclear located mutant Huntingtin alters the function of the ER, several reports indicate that mutant Huntingtin affects many essential processes related to the secretory pathway, including inhibition of ER-associated degradation, altered ER/Golgi vesicular trafficking and axonal transport, disrupted autophagy and abnormal ER calcium homeostasis. All these alterations are predicted to have a common pathological outcome associated to disturbance of protein folding and maturation pathways at the ER, generating chronic ER stress and neuronal dysfunction. Here, we review recent evidence involving ER stress in HD pathogenesis and discuss possible therapeutic strategies to target organelle function in the context of disease.

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Available from: René L Vidal, Nov 24, 2014
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    • ". In accordance, it was demonstrated that mutant htt interacts with the ubiquitin ligase HRD1 and this interaction inhibits the ERAD and triggers ER stress [171] [175] [176]. An impaired IP3R- GRP78 interaction was observed in the brain of a HD mice model suggesting that altered ER calcium signals promote neuronal cell death in this neurodegenerative disease [177]. "
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    ABSTRACT: Neurodegenerative disorders such as Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, several evidences support 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.
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    • "ER stress alters cellular iron homeostasis by inducing hepcidin expression [33] [34]. Altered iron homeostasis and ER stress are associated with chronic neurodegenerative diseases such as Huntington's disease and Alzheimer's disease [35] [36]. It is not known whether ER stress also affects BDH2 expression. "
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    ABSTRACT: Macrophages play a very important role in host defense and in iron homeostasis by engulfing senescent red blood cells and recycling iron. Hepcidin is the master iron regulating hormone that limits dietary iron absorption from the gut and limits iron egress from macrophages. Upon infection macrophages retain iron to limit its bioavailability which limits bacterial growth. Recently, a short chain butyrate dehydrogenase type 2 (BDH2) protein was reported to contain an iron responsive element and to mediate cellular iron trafficking by catalyzing the synthesis of the mammalian siderophore that binds labile iron; therefore, BDH2 plays a crucial role in intracellular iron homeostasis. However, BDH2 expression and regulation in macrophages have not yet been described. Here we show that LPS-induced inflammation combined with ER stress led to massive BDH2 downregulation, increased the expression of ER stress markers, upregulated hepcidin expression, downregulated ferroportin expression, caused iron retention in macrophages, and dysregulated cytokine release from macrophages. We also show that ER stress combined with inflammation synergistically upregulated the expression of the iron carrier protein NGAL and the stress-inducible heme degrading enzyme heme oxygenase-1 (HO-1) leading to iron liberation. This is the first report to show that inflammation and ER stress downregulate the expression of BDH2 in human THP-1 macrophages.
    Full-text · Article · Dec 2014 · Journal of Immunology Research
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    • "Stress signals culminate in overloading ER with proteins and exhausting the ER machinery. ER stress is thought to be and in certain cases proved to play a key role in diseases like Alzheimer’s disease (Salminen et al., 2009; Viana et al., 2012), Parkinson’s disease (Wang and Takahashi, 2007; Cali et al., 2011), amyotrophic lateral sclerosis (ALS) (Lautenschlaeger et al., 2012; Tadic et al., 2014), poly glutamine diseases (Vidal et al., 2011), ischemia (Doroudgar et al., 2009), atherosclerosis (Zhou and Tabas, 2013), bipolar disorder (Hayashi et al., 2009), prion diseases (Xu and Zhu, 2012), cancer (Tsai and Weissman, 2010), diabetes (Papa, 2012), auto immune disorders (Zhong et al., 2012), and cardiovascular disorders (Minamino et al., 2010). Interestingly, there are reports demonstrating that ER stress inhibition could protect against neuronal injury (Qi et al., 2004; Sokka et al., 2007), ischemia (Nakka et al., 2010), cardiovascular diseases (Teng et al., 2011), respiratory disorders (Hoffman et al., 2013), atherosclerosis (Zhou et al., 2013), and sleep apnea (Zhu et al., 2008), in in vivo murine models. "
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    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.
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