Endoplasmic reticulum dysfunction in neurological disease

Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
The Lancet Neurology (Impact Factor: 21.9). 01/2013; 12(1):105-18. DOI: 10.1016/S1474-4422(12)70238-7
Source: PubMed


Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurological disorders, including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurological disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognised but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible.

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    • "In the CNS, ER stress has been associated with neuronal death in neurodegenerative diseases (Stefani et al., 2012; Roussel et al., 2013), and there is now increasing evidence that ER stress plays a crucial role in hypoxia/ischaemiainduced cell death in vitro (Chen et al., 2008; Roussel et al., 2013) and in vivo (Galehdar et al., 2010; Stefani et al., 2012). "
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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. Experimental approach: 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. Key results: 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.
    British Journal of Pharmacology 01/2015; 172(11). DOI:10.1111/bph.13095 · 4.84 Impact Factor
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    • "Hence, this is a key transcription factor mediating antioxidative responses and therapeutic fortification of Nrf2 has become a promising strategy to protect oligodendrocytes and neurons from ROS toxicity and glutamate evoked excitotoxicity (Gonsette, 2008) to prevent demyelination , axonal loss and neuronal death. Alternative strategies are ROS scavenging (Sun et al., 2013), so far not that successful because the scavengers do not sufficiently reach the CNS, or prevention of pathological ROS generation, the latter mainly caused by malfunctioning mitochondria (Nikic et al., 2011; Witte et al., 2014), stress of the endoplasmic reticulum (McMahon et al., 2012; Roussel et al., 2013) and upregulation of pro-oxidative enzymes including nitric oxide synthases (NOS), cyclooxygenases, NADPH oxidases (NOX), lipoxygenases and lipid peroxidases that are all highly expressed in activated microglia, macrophages and neutrophils in active MS lesions (Haider et al., 2011; Lassmann & van Horssen, 2011; Friese et al., 2014). Superoxide and peroxynitrite, produced by NOXs and uncoupled NOSs, lead to demyelination and axonal damage because lipids, proteins and nucleic acids become targets of peroxidation and nitration. "
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    ABSTRACT: The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli, sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.015 · 9.72 Impact Factor
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    • "In addition, in several systemic amyloidosis the burden of tissue-deposited material can, by itself, damage organs simply by hindering a proper flow of nutrients to the cells [27]. That oxidative stress and alteration in intracellular Ca 21 levels play a key role in damaging cells exposed to early aggregates is suggested by many experimental data [17] [18] [19] [20] [21] [22]. Cell treatment with antioxidants such as tocopherol, lipoic acid, reduced glutathione or phenolic substances is protective against aggregate toxicity [28] [29]. "
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    ABSTRACT: Mediterranean and Asian diets are currently considered as the most healthy traditional feeding habits effective against risk of age-associated, particularly cardiovascular and neurodegenerative, diseases. A common feature of these two regimens is the abundance of foods and beverages of plant origin (green tea, extra virgin olive oil, red wine, spices, berries, and aromatic herbs) that are considered responsible for the observed beneficial effects. Epidemiological data suggest that the phenolic component remarkably enriched in these foods plays an important role in reducing the incidence of amyloid diseases, pathological conditions associated to tissue deposition of toxic protein aggregates responsible for progressive functional deterioration. Great effort is being spent to provide knowledge on the effects of several natural phenols in this context, moving from the test tube to animal models and, more slowly, to the patient's bed. An emerging feature that makes these molecules increasingly attractive for amyloid disease prevention and therapy is their wide spectrum of activity: recent pieces of evidence suggest that they can inhibit the production of amyloidogenic peptides from precursors, increase antioxidant enzyme activity, activate autophagy and reduce inflammation. Our concept should than shift from considering natural phenols simply as antioxidants or, at the best, as amyloid aggregation inhibitors, to describing them as potentially multitargeting drugs. A main concern is the low bioavailability of such compounds and efforts aimed at improving it are underway, with encapsulation strategies being the most promising ones. © 2014 BioFactors, 00(00):000–000, 2014
    BioFactors 09/2014; 40(5). DOI:10.1002/biof.1171 · 4.59 Impact Factor
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