Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases

Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute,10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell death and differentiation (Impact Factor: 8.18). 05/2011; 18(9):1478-86. DOI: 10.1038/cdd.2011.65
Source: PubMed


The pathological processes of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases engender synaptic and neuronal cell damage. While mild oxidative and nitrosative (nitric oxide (NO)-related) stress mediates normal neuronal signaling, excessive accumulation of these free radicals is linked to neuronal cell injury or death. In neurons, N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and subsequent Ca(2+) influx can induce the generation of NO via neuronal NO synthase. Emerging evidence has demonstrated that S-nitrosylation, representing covalent reaction of an NO group with a critical protein thiol, mediates the vast majority of NO signaling. Analogous to phosphorylation and other posttranslational modifications, S-nitrosylation can regulate the biological activity of many proteins. Here, we discuss recent studies that implicate neuropathogenic roles of S-nitrosylation in protein misfolding, mitochondrial dysfunction, synaptic injury, and eventual neuronal loss. Among a growing number of S-nitrosylated proteins that contribute to disease pathogenesis, in this review we focus on S-nitrosylated protein-disulfide isomerase (forming SNO-PDI) and dynamin-related protein 1 (forming SNO-Drp1). Furthermore, we describe drugs, such as memantine and newer derivatives of this compound that can prevent both hyperactivation of extrasynaptic NMDARs as well as downstream pathways that lead to nitrosative stress, synaptic damage, and neuronal loss.

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    • "This in turn could influence the way oxidized proteins interact with other proteins in the complex cellular milieu. In some cases, posttranslational modifications can lead to protein aggregation and misfolding and act as a trigger of cell death [156] [157]. S-nitrosation of proteins has been recognized as a marker of aging and Alzheimer's disease [158] [159]. "
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    ABSTRACT: The role of nitric oxide in the pathogenesis and progression of neurodegenerative illnesses such as Parkinson's and Alzheimer's diseases has become prominent over the years. Increased activity of the enzymes that produce reactive oxygen species, decreased activity of antioxidant enzymes and imbalances in glutathione pools mediate and mark the neurodegenerative process. Much of the oxidative damage inflicted on proteins is brought about by the production of nitric oxide by nitric oxide synthases (NOS) and the subsequent reactivity of nitric oxide with reactive oxygen species. Proteomic methods have advanced the field tremendously, by facilitating the quantitative assessment of differential expression patterns and oxidative modifications of proteins and alongside, mapping their non-canonical functions. As a signaling molecule involved in multiple biochemical pathways, the level of nitric oxide is subject to tight regulation. All three NOS isoforms display aberrant patterns of expression in Alzheimer's disease, altering intracellular signaling and routing oxidative stress in directions that are uncompounded. This review discusses the prime factors that control nitric oxide biosynthesis, reactivity footprints and ensuing effects in the development of neurodegenerative diseases.
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    • ", 2013 ) . At the same time the excessive generation of reactive nitrogen species ( RNS ) , including nitric oxide ( NO ) contributes to cell death in neurodegener - ative diseases ( Nakamura and Lipton , 2011 ) . Different stable compounds such as malondialdehyde ( MDA ) and glutathione ; and the activity of antioxidant enzymes such as catalase ( CAT ) and superoxide dismutase ( SOD ) can be used as oxidative stress indicators ( Gonzaíez et al . "
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    ABSTRACT: Early degeneration of pedunculopontine nucleus (PPN) is considered part of the changes that characterize premotor stages of Parkinson's disease (PD). In this paper, the effect of unilateral neurotoxic lesion of PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). Nigral and striatal redox balance, was studied by means of biochemical indicators such as malondialdehyde (MDA), nitric oxide (NO) and the catalase enzymatic activity (CAT EA). Lesioned rats showed fine motor dysfunction expressed both as an increase in the length (p<0.001) and deviation (p<0.001) of the traveled path and also in the time spent (p<0.01) in the circular small beam (CBS) (p<0.01) in comparison with control groups. In addition, the lesioned rats group presented a right asymmetry index greater than 0.5 which is consistent with a significant increase in the percentage of use of the right forelimb (ipsilateral to the lesion), compared with control group (p<0.05). Biochemical studies revealed that after 48h PPN neurotoxic injury, the CAT EA showed a significant increase in the subtantia nigra pars compacta (SNpc) (p<0.05). This significant increase of CAT EA persisted in the nigral tissue (p<0.001) and reached the striatal tissue (p<0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA (p<0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum) was found. The events associated with the generation of free radicals at nigral and striatal level, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Full-text · Article · Jan 2015 · Neuroscience
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    • "Pathophysiology is correlated with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to not only the loss of or enhanced nitric oxide synthase activity but also the denitrosylation by a major denitrosylase, S-nitrosoglutathione reductase (GSNOR) [1]. Abnormal protein S-nitrosylation causes many diseases such as cardiovascular, musculoskeletal, and neurological dysfunction [7]. Furthermore, autophagy, a vacuolar degradation for long-lived and aggregate-prone proteins, plays an important role in neurodegeneration. "
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    ABSTRACT: Arsenic is a class I human carcinogen (such as inducing skin cancer) by its prominent chemical interaction with protein thio (-SH) group. Therefore, arsenic may compromise protein S-nitrosylation by competing the -SH binding activity. In the present study, we aimed to understand the influence of arsenic on protein S-nitrosylation and the following proteomic changes. By using primary human skin keratinocyte, we found that arsenic treatment decreased the level of protein S-nitrosylation. This was coincident to the decent expressions of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). By using LC-MS/MS, around twenty S-nitrosoproteins were detected in the biotin-switched eluent. With the interest that arsenic not only regulates posttranslational S-nitrosylation but also separately affects protein's translation expression, we performed two-dimensional gel electrophoresis and found that 8 proteins were significantly decreased during arsenic treatment. Whether these decreased proteins are the consequence of protein S-nitrosylation will be further investigated. Taken together, these results provide a finding that arsenic can deplete the binding activity of NO and therefore reduce protein S-nitrosylation.
    Full-text · Article · Jul 2014
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