The Role of ER Stress-Induced Apoptosis in Neurodegeneration
Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UK. Current Alzheimer research
(Impact Factor: 3.89).
01/2012; 9(3):373-87. DOI: 10.2174/156720512800107618
Post-mortem analyses of human brain tissue samples from patients suffering from neurodegenerative disorders have demonstrated dysfunction of the endoplasmic reticulum (ER). A common characteristic of the aforementioned disorders is the intracellular accumulation and aggregation of proteins due to genetic mutations or exogenous factors, leading to the activation of a stress mechanism known as the unfolded protein response (UPR). This mechanism aims to restore cellular homeostasis, however, if prolonged, can trigger pro-apoptotic signals, which are thought to contribute to neuronal cell death. The authors present evidence to support the role of ER stress-induced apoptosis in Alzheimer's, Parkinson's and Huntington's diseases, and further examine the interplay between ER dyshomeostasis and mitochondrial dysfunction, and the function of reactive oxygen species (ROS) and calcium ions (Ca(2+)) in the intricate relationship between the two organelles. Possible treatments for neurodegenerative diseases that are based on combating ER stress are finally presented.
Available from: sciencedirect.com
- "The major symptoms involve motor dysfunction (reviewed in ). One of the mechanisms that affect the survival of dopaminergic neurons in Parkinson's disease is associated with dysregulation of Ca 2+ levels, especially in the ER and mitochondria . One of the consequences of perturbing Ca 2+ homeostasis is the accumulation of unfolded/misfolded proteins in the ER lumen. "
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ABSTRACT: In this review we describe the present knowledge about store operated Ca2 + entry (SOCE) in neurons and the proteins involved in this process: STIM, as well as Orai and TRP channels. We address the issue of whether SOCE is used only to refill Ca2 + in the ER or whether Ca2 + that enters the neuronal cell during SOCE also performs signaling functions. We collected the data indicating that SOCE and its components participate in the important processes in neurons. This has implications for identifying new drug targets for the treatment of brain diseases. Evidence indicates that in neurodegenerative diseases Ca2 + homeostasis and SOCE components become dysregulated. Thus, different targets and strategies might be identified for the potential treatment of these diseases. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.
Available from: onlinelibrary.wiley.com
- "In the ischaemic penumbra, translational arrest induced by PERK-mediated phosphorylation of eIF2α is associated with cell survival (Liu et al., 2006), whereas dephosphorylation of eIF2α observed under prolonged ER stress seems to promote neuronal apoptosis through activation of C/EBP homologous protein (CHOP) and caspase 12 (Galehdar et al., 2010; Stefani et al., 2012). Paradoxically, it has also been reported that phosphorylation of eIF2α results in neuronal death (Halterman et al., 2008; Binet et al., 2013) whereas delayed CHOP expression protects neurons against hypoxic injury (Halterman et al., 2010). "
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ABSTRACT: Background and purpose:
Hypoxia inducible factor-1 (HIF-1) promotes transitory neuronal survival suggesting that additional mechanisms such as the endoplasmic reticulum (ER) stress might be involved in determining neuronal survival or death. Here, we examined the involvement of ER stress in hypoxia-induced neuronal death and analysed the relationship between ER stress and the HIF-1 pathways.
Cultures of rat cortical neurons were exposed to chemical hypoxia induced by 200 μM CoCl2 , and its effect on neuronal viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and counting apoptotic nuclei. Protein levels were determined by Western blot analysis. RT-PCR was performed to analyse the content and the t1/2 of HIF-1α mRNA.
Chemical hypoxia induced neuronal apoptosis in a time-dependent manner and activated the ER stress PRK-like endoplasmic reticulum kinase (PERK)-dependent pathway. At later stages, chemical hypoxia increased the expression of the C/EBP homologous protein (CHOP) and caspase 12 activity. CoCl2 reduced HIF-1α mRNA t1/2 leading to a decrease in HIF-1α mRNA and protein content, simultaneously activating the ER stress PERK-dependent pathway. Salubrinal, a selective inhibitor of phospho-eIF2α phosphatase, protected neurons from chemical hypoxia by reducing CHOP levels and caspase 12 activity, and increasing the t1/2 of HIF-1α mRNA and the levels of HIF-1α protein. Knocking down HIF-1α blocked the neuroprotective effects of salubrinal.
Conclusions and implications:
Neuronal apoptosis induced by chemical hypoxia is a process regulated by HIF-1α stabilization early on and by ER stress activation at later stages. Our data also suggested that HIF-1α levels were regulated by ER stress.
Available from: Nigel H Greig
- "In this regard, a wide range of inflammatory markers, either absent or minimally expressed in the healthly population, have been found present in AD, MS, PD, HD, ALS and MSA –. Additionally, oxidative stress, marked by lipid peroxidation, nitration, reactive carbonyls, and nucleic acid oxidation, is perhaps the earliest feature of neurodegeneration ,  and occurs in vulnerable neurons preceding any defining classical pathology. "
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ABSTRACT: Neurodegenerative diseases comprise both hereditary and sporadic conditions characterized by an identifying progressive nervous system dysfunction and distinctive neuopathophysiology. The majority are of non-familial etiology and hence environmental factors and lifestyle play key roles in their pathogenesis. The extensive use of and ever increasing worldwide demand for electricity has stimulated societal and scientific interest on the environmental exposure to low frequency electromagnetic fields (EMFs) on human health. Epidemiological studies suggest a positive association between 50/60-Hz power transmission fields and leukemia or lymphoma development. Consequent to the association between EMFs and induction of oxidative stress, concerns relating to development of neurodegenerative diseases, such as Alzheimer disease (AD), have been voiced as the brain consumes the greatest fraction of oxygen and is particularly vulnerable to oxidative stress. Exposure to extremely low frequency (ELF)-EMFs are reported to alter animal behavior and modulate biological variables, including gene expression, regulation of cell survival, promotion of cellular differentiation, and changes in cerebral blood flow in aged AD transgenic mice. Alterations in inflammatory responses have also been reported, but how these actions impact human health remains unknown. We hence evaluated the effects of an electromagnetic wave (magnetic field intensity 1mT; frequency, 50-Hz) on a well-characterized immortalized neuronal cell model, human SH-SY5Y cells. ELF-EMF exposure elevated the expession of NOS and O2-, which were countered by compensatory changes in antioxidant catylase (CAT) activity and enzymatic kinetic parameters related to CYP-450 and CAT activity. Actions of ELF-EMFs on cytokine gene expression were additionally evaluated and found rapidly modified. Confronted with co-exposure to H2O2-induced oxidative stress, ELF-EMF proved not as well counteracted and resulted in a decline in CAT activity and a rise in O2- levels. Together these studies support the further evaluation of ELF-EMF exposure in cellular and in vivo preclinical models to define mechanisms potentially impacted in humans.
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