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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    • "At physiological levels, NO is essential for neuronal function, differentiation and survival through activation of signalling pathways that include the cyclic guanosine monophosphate (cGMP)/soluble guanylyl cyclase pathway [4] and S-nitrosylation, in which NO reversibly binds to thiol groups of proteins [5]. The vast network of NO-associated signalling paradigms further includes acetylation/deacetylation and methylation/demethylation modifications and peroxynitrite formation (leading to nitrotyrosination of protein residues), as well as modulation of gene expression via epigenetic changes [5] [6] [7] [8]. How controlled Snitrosylation/nitrotyrosination of proteins and activation of the NO/cGMP signalling pathway promote cellular survival and induce epigenetic changes while uncontrolled signalling promotes cell death and dysfunction remains to be elucidated . "

    Oxidative Medicine and Cellular Longevity 10/2015; · 3.36 Impact Factor
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    • "Indeed, an increasing number of studies have linked excessive protein Snitrosylation to the pathogenesis of chronic and degenerative diseases, including cardiovascular disease, stroke, and neurological disorders [81]. In particular, aberrant S-nitrosylation, involving dozens of proteins , is associated with neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease [82] [83]. Hyper-Snitrosylation of multiple proteins is also implicated in metabolic diseases such as diabetes and obesity [84] [85] [86]. "
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    ABSTRACT: Background: The free radical nitric oxide (NO) and the thiol oxidoreductase thioredoxin (Trx) play essential roles in cellular redox regulation. Recent biochemical and cellular studies have revealed a complex thiol-dependent crosstalk between NO and Trx that modulates multiple redox-dependent pathways. Scope of review: This review aims to discuss recent progress, as well as the remaining questions, regarding the interaction and cross regulation between NO and Trx in cellular function and dysfunction. Major conclusions: The importance and ubiquity of NO-mediated S-nitrosylation of protein thiols as a signaling mechanism is increasingly recognized as is the central role of Trx in regulating S-nitrosylation processes. By denitrosylating diverse protein substrates, Trx plays an active role in attenuating NO signaling as well as in ameliorating nitrosative stress. Yet, at the same time, Trx can also support the activity of NO synthases, thus promoting NO production and its downstream effects. Finally, NO can reciprocally modulate the redox activity of Trx and Trx reductase. General significance: Further elucidation of the crosstalk between NO and Trx will be important for an improved understanding of the effects of reactive oxygen and nitrogen species on cellular signaling and function.
    Biochimica et Biophysica Acta 09/2015; 1850(12). DOI:10.1016/j.bbagen.2015.09.010 · 4.66 Impact Factor
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    • "Although S-nitrosylation is known to regulate various physiological processes [1] [2], recent evidence suggests that dysregulated, usually elevated, S-nitrosylation could be involved in cellular dysfunction and chronic disorders such as Alzheimer and Parkinson diseases, obesity, and type 2 diabetes [3] [4]. A constitutive increase in S-nitrosylation frequently interferes with protein function; consequently it can disrupt various cellular processes and thereby cause cell damage and degenerative changes. "
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    ABSTRACT: S-nitrosylation, the coupling of a nitric oxide moiety to a reactive cysteine residue to form an S-nitrosothiol (SNO), is an important posttranslational mechanism for regulating protein activity. Growing evidence indicates that hyper-S-nitrosylation may contribute to cellular dysfunction associated with various human diseases. It is also increasingly appreciated that thioredoxin and thioredoxin reductase play significant roles in the cellular catabolism of SNO and protection from nitrosative stress. Here, we investigated the SNO reductase activity and protective effects of thioredoxin-mimetic peptides (TXMs), Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4), both under cell-free conditions and in nitrosatively stressed cultured cells. In vitro biochemical analyses revealed that the TXM peptides reduced small-molecule SNO compounds, such as S-nitrosoglutathione (GSNO), and acted as general and efficient protein-denitrosylating agents. In particular, CB3 was found to be a highly potent SNO-metabolizing agent. Notably, CB3 mimicked the activity of thioredoxin by coupling with thioredoxin reductase to enhance GSNO reduction. Moreover, in a cell-free lysate system, both CB3 and CB4 synergized with an NADPH-dependent activity to denitrosylate proteins. Further investigation revealed that the TXM peptides protect the peroxiredoxin-thioredoxin system from SNO-dependent inhibition. Indeed, SNO-inhibited Prx1 was efficiently denitrosylated and reactivated by CB3 or CB4. In addition, CB3 protected thioredoxin reductase from SNO-mediated inactivation both in vitro and in intact cells. Finally, CB3 and CB4 partially rescued human neuroblastoma SH-SY5Y cells and rat insulinoma INS-1 832/13 cells from GSNO-induced growth inhibition. Collectively, the present findings indicate the efficient denitrosylation activity and protective effects of TXM peptides and suggest their potential therapeutic value in treating pathological conditions related to nitrosative stress.
    Free Radical Biology and Medicine 12/2014; 79. DOI:10.1016/j.freeradbiomed.2014.11.021 · 5.74 Impact Factor
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