Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

Del E. Web Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: .
Neuron (Impact Factor: 15.05). 05/2013; 78(4):596-614. DOI: 10.1016/j.neuron.2013.05.005
Source: PubMed


S-Nitrosylation is a redox-mediated posttranslational modification that regulates protein function via covalent reaction of nitric oxide (NO)-related species with a cysteine thiol group on the target protein. Under physiological conditions, S-nitrosylation can be an important modulator of signal transduction pathways, akin to phosphorylation. However, with aging or environmental toxins that generate excessive NO, aberrant S-nitrosylation reactions can occur and affect protein misfolding, mitochondrial fragmentation, synaptic function, apoptosis or autophagy. Here, we discuss how aberrantly S-nitrosylated proteins (SNO-proteins) play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Insight into the pathophysiological role of aberrant S-nitrosylation pathways will enhance our understanding of molecular mechanisms leading to neurodegenerative diseases and point to potential therapeutic interventions.

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    • "Each of the three NOS isoforms have been postulated to play a role in either AD progression or prevention, leading to a seemingly conflicting message about the role of NO in AD and whether NO is neuroprotective or neurotoxic. The signaling pathways of NO converge on three main cellular effects, all of which have been identified to play a role in AD: signaling via soluble guanylate cyclase and the cyclic guanosine monophosphate (cGMP) pathway (Santhanam et al., 2015); direct S-nitrosylation of protein cysteine residues (addition of a nitrosyl ion NO− to generate a nitrosothiol, RS-N=O) (reviewed in (Nakamura et al., 2013)); and protein tyrosine nitration (addition of nitrogen dioxide NO 2 to generate 3-nitrotyrosine) (Hensley et al., 1998). Diversion of NO signaling towards one of these pathways over another depends on the local cellular microenvironment, including levels of transition metal complexes and redox status (Thomas et al., 2002). "
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    ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder involving the loss of neurons in the brain which leads to progressive memory loss and behavioral changes. To date, there are only limited medications for AD and no known cure. Nitric oxide (NO) has long been considered part of the neurotoxic insult caused by neuroinflammation in the Alzheimer’s brain. However, focusing on early developments, prior to the appearance of cognitive symptoms, is changing that perception. This has highlighted a compensatory, neuroprotective role for NO that protects synapses by increasing neuronal excitability. A potential mechanism for augmentation of excitability by NO is via modulation of voltage-gated potassium channel activity (Kv7 and Kv2). Identification of the ionic mechanisms and signaling pathways that mediate this protection is an important next step for the field. Harnessing the protective role of NO and related signaling pathways could provide a therapeutic avenue that prevents synapse loss early in disease.
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    • "Therefore, it has to be considered that H 2 S is not working on its own but rather in concert with a host of other reactive chemicals (Hancock & Whiteman, 2014 ). Therefore, similar investigations of thiol modifications needs to be carried out with other compounds, perhaps with other assays too, such as the biotin switch assay (Forrester et al., 2009; Haldar & Stamler, 2013; Nakamura et al., 2013; Zhang et al., 2005), as it is under the physiological conditions in which a protein resides that will determine the exact end result of the thiol alteration. If NO is the predominant signal, then perhaps S-nitrosylation will be the result, but if H 2 O 2 is predominant then the thiol may be oxidized—to varying degrees. "
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    ABSTRACT: Hydrogen sulfide (H2S) is an important gasotransmitter in both animals and plants. Many physiological events, including responses to stress, have been suggested to involve H2S, at least in part. On the other hand, numerous responses have been reported following treatment with H2S, including changes in the levels of antioxidants and the activities of transcription factors. Therefore, it is important to understand and unravel the events that are taking place downstream of H2S in signaling pathways. H2S is known to interact with other reactive signaling molecules such as reactive oxygen species (ROS) and nitric oxide (NO). One of the mechanisms by which ROS and NO have effects in a cell is the modification of thiol groups on proteins, by oxidation or S-nitrosylation, respectively. Recently, it has been reported that H2S can also modify thiols. Here we report a method for the determination of thiol modifications on proteins following the treatment with biological samples with H2S donors. Here, the nematode Caenorhabditis elegans is used as a model system but this method can be used for samples from other animals or plants. © 2015 Elsevier Inc. All rights reserved.
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    • "S-glutathionylation has both inactivating effects on the function of proteins, but protective effects against irreversible damage of proteins in other condi- tions[161]. Finally, S-nitrosylation of proteins has been related to aging and age-associated neurodegenerative diseases[162]. Succination in age-related disease has not been studied in great detail, but mitochondria are important sites for hydrogen sulfide metabolism and have high sensitivity to hydrogen sulfide signaling[163]. "
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    ABSTRACT: Reactive species have been regarded as by-products of cellular metabolism, which cause oxidative damage contributing to aging and neurodegenerative diseases. However, accumulated evidence support the notion that reactive species mediate intracellular and extracellular signals that regulate physiological functions including posttranslational protein modifications. Cysteine thiol groups of proteins are particularly susceptible to oxidative modifications by oxygen, nitrogen and sulfur species generating different products with critical roles in the cellular redox homeostasis. At physiological conditions, reactive species can function not only as intracellular second messengers with regulatory roles in many cellular metabolic processes, but also as part of an ancestral biochemical network that control cellular survival, regeneration and death. This biochemical network, called cellular cysteine network (CYSTEINET), is proposed to be dysregulated in some neurodegenerative diseases. Due to the fact that there are many cysteine-bearing proteins and cysteine-dependent enzymes susceptible to oxidative modifications, it is proposed that oxidative-changed proteins at cysteine residues may be critical for Parkinson's disease development. In the present review, I advance the concept that "cysteinet" is impaired in Parkinson's disease resulting in a functional and structural dysregulation of the matrix of interconnected cysteine-bearing proteins, which in conjunction with reactive species and glutathione regulate the cellular bioenergetic metabolism, the redox homeostasis and the cellular survival. This network may represent an ancestral down-top system composed by a complex matrix of proteins with very different cellular functions, but bearing the same regulatory thiol radical. Finally, the possible role of N-acetylcysteine and derivatives to regulate "cysteinet" and slow down Parkinson's disease development and progression is discussed.
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