An increase in S‐glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach

Newman, Shelley F.; Sultana, Rukhsana; Perluigi, Marzia; Coccia, Raffaella; Cai, Jian; Pierce, William M.; Klein, Jon B.; Turner, Delano M.; Butterfield, D. Allan

doi:10.1002/jnr.21275

Cited by 159 publications

(118 citation statements)

References 65 publications

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“…4c). Indeed six of the 10 proteins found to contain an HNO-induced modification in this study have previously been reported with redox-based modifications on their cysteine residues often in pathological or stressed situations leading to alterations in protein function (actin (41)(42)(43), ␣-enolase (44), GAPDH (21,45,46), integrin ␤3 (47-49), pyruvate kinase isozyme (50), and vinculin (51)). Redox regulation of cysteine residues has emerged over recent years as a key modulator of protein function, and recently evidence has begun to come to light regarding the processes involved in regulating these redox-based post-translational modifications, showing that many of these are specific and reversible modifications that play a key role in protein function.…”

Section: Global Proteome Analysis For Discovery Of Hno-induced Modifimentioning

confidence: 73%

Identification of Nitroxyl-induced Modifications in Human Platelet Proteins Using a Novel Mass Spectrometric Detection Method

Hoffman

Walsh

Rogalski

et al. 2009

Molecular & Cellular Proteomics

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Nitroxyl (HNO) exhibits many important pharmacological effects, including inhibition of platelet aggregation, and the HNO donor Angeli's salt has been proposed as a potential therapeutic agent in the treatment of many diseases including heart failure and alcoholism. Despite this, little is known about the mechanism of action of HNO, and its effects are rarely linked to specific protein targets of HNO or to the actual chemical changes that proteins undergo when in contact with HNO. Here we study the presumed major molecular target of HNO within the body: protein thiols. Cysteine-containing tryptic peptides were reacted with HNO, generating the sulfinamide modification and, to a lesser extent, disulfide linkages with no other long lived intermediates or side products. The sulfinamide modification was subjected to a comprehensive tandem mass spectrometric analysis including MS/MS by CID and electron capture dissociation as well as an MS 3 analysis. These studies revealed a characteristic neutral loss of HS(O)NH 2 (65 Da) that is liberated from the modified cysteine upon CID and can be monitored by mass spectrometry. Upon storage, partial conversion of the sulfinamide to sulfinic acid was observed, leading to coinciding neutral losses of 65 and 66 Da (HS(O)OH). Validation of the method was conducted using a targeted study of nitroxylated glyceraldehyde-3-phosphate dehydrogenase extracted from Angeli's salt-treated human platelets. In these ex vivo experiments, the sample preparation process resulted in complete conversion of sulfinamide to sulfinic acid, making this the sole subject of further ex vivo studies. A global proteomics analysis to discover platelet proteins that carry nitroxyl-induced modifications and a mass spectrometric HNO dose-response analysis of the modified proteins were conducted to gain insight into the specificity and selectivity of this modification. These methods identified 10 proteins that are modified dose dependently in response to HNO, whose functions range from metabolism and cytoskeletal rearrangement to signal transduction, providing for Nitric oxide (NO)1 has emerged as an important physiological signaling molecule, particularly in the vascular, neuronal, and immune systems. NO regulates many processes including platelet function, vascular tone, and leukocyte recruitment mainly through the cGMP second messenger system (1). More recent studies have shown that nitric oxide can react directly with a number of different biological species including metal centers of proteins, nucleophilic amino acid residues (nitrosation/S-nitrosylation), and aromatic amino acid residues (nitration) (2, 3), and the products of these reactions have been analyzed by mass spectrometry (4 -8). The biological relevance of these reactions is slowly coming to light, and NO-mediated S-nitrosylation has now been linked to a number of diseases including diabetes, multiple sclerosis, cystic fibrosis, and asthma (9).Nitroxyl (HNO/NO Ϫ ), an alternative redox form of NO, has only recently begun to draw attention in th...

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Section: Global Proteome Analysis For Discovery Of Hno-induced Modifimentioning

confidence: 73%

Identification of Nitroxyl-induced Modifications in Human Platelet Proteins Using a Novel Mass Spectrometric Detection Method

Hoffman

Walsh

Rogalski

et al. 2009

Molecular & Cellular Proteomics

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“…141 In addition, increased protein glutathionylation (protein-SSG) has been reported during AD, which is associated with increased oxidative stress. 142 Accordingly, GRX1 overexpression protects against amyloid b-induced toxicity. 143 PD progression is associated with a depletion of GSH levels and an increase in ROS formation in the substantia nigra.…”

Section: Gsh Apoptosis and Disease Progressionmentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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“…Several signaling proteins have been shown to undergo glutathionylation, including PTPs and transcription factors (36,63,(77)(78)(79)(80). Although the mechanism by which glutathionylation occurs is not agreed upon, this process has been shown occur in vivo in relevant cell types (81)(82)(83)(84)(85)(86). Although glutathionylation of PTP1B can be achieved in vitro with the purified enzyme through oxidation by H 2 O 2 and addition of GSH (through the sulfenic acid and sulfenyl-amide as described above) (26) (27) or by addition of a very high concentration of GSSG (63), it is not known if glutathionylation occurs enzymatically or non-enzymatically in vivo and kinetic considerations clearly argue against the latter (87).…”

Section: A Signaling Proteins In Which Critical Cysteines Are Modifiedmentioning

confidence: 99%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

219

165

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During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

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An increase in S‐glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach

Cited by 159 publications

References 65 publications

Identification of Nitroxyl-induced Modifications in Human Platelet Proteins Using a Novel Mass Spectrometric Detection Method

Identification of Nitroxyl-induced Modifications in Human Platelet Proteins Using a Novel Mass Spectrometric Detection Method

Apoptosis and glutathione: beyond an antioxidant

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

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