Decreased expression and increased oxidation of plasma haptoglobin in Alzheimer disease: Insights from redox proteomics

Cocciolo, Annalisa; Domenico, Fabio Di; Coccia, Raffaella; Fiorini, Ada; Cai, Jian; Pierce, William M.; Mecocci, Patrizia; Butterfield, D. Allan; Perluigi, Marzia

doi:10.1016/j.freeradbiomed.2012.08.596

Cited by 60 publications

(45 citation statements)

References 52 publications

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“…It has been shown that hypochlorite generated by stimulated neutrophils induces dissociation of α 2 M in vitro (26), and increased oxidation of α 2 M has been detected in rheumatoid ar- thritis and Alzheimer's disease (27,44), two protein misfolding conditions in which myeloperoxidase activity is known to be elevated (5, 45). Furthermore, our experiments in whole-blood plasma confirm that, in complex biological fluids, α 2 M is readily induced to dissociate into dimers by low, physiologically relevant hypochlorite concentrations (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer's disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human α 2 -macroglobulin (α 2 M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric α 2 M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified α 2 M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid β-peptide (Aβ 1-42 ). Here, we show that hypochlorite-modified α 2 M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Aβ 1-42 neurotoxicity. Our results support the conclusion that α 2 M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity. molecular chaperone | inflammation | protein folding | clearance H ypochlorite, a potent oxidant produced by immune cells through the myeloperoxidase-H 2 O 2 -chloride system, kills invading microbes predominately by inducing the misfolding and aggregation of their proteins (1). The effects of hypochlorite, however, are nonspecific; therefore, when generated in vivo, the host organism suffers collateral damage (reviewed in refs. 2 and 3). During inflammation, hypochlorite production is accompanied by additional stresses, which are themselves capable of inducing protein misfolding (e.g., increased temperature and lowered pH); it is, therefore, not surprising that, in a large number of diseases [e.g., atherosclerosis (4), Alzheimer's disease (5, 6), age-related macular degeneration (7), and arthritis (8)], inflammatory pathology is associated with the accumulation of misfolded proteins.α 2 -Macroglobulin (α 2 M) is a highly abundant secreted protein that is best known for its ability to trap proteases (9); α 2 M can, however, interact with a broad range of molecules, and consequently, many other biological roles have been suggested, including targeting cytokines for clearance, sequestration of zinc, and opsonization of bacteria (reviewed in ref. 10). Furthermore, α 2 M has been identified as one of a small number of abundant extracellular chaperones (11). Although our un...

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Section: Discussionmentioning

confidence: 99%

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In terms of irreversible oxidative damage, redox proteomics studies on oxidatively damaged proteins by the Butterfield's group have found, increased carbonylation in some circulating protein in Alzheimer Disease, including haptoglobin β chain, serotransferrin and α2-Macroglobulin (28).…”

Section: Secretion Of Carbonylated Proteinsmentioning

confidence: 99%

Redox Proteomics Applied to the Thiol Secretome

Ghezzi

Chan

2017

Antioxidants & Redox Signaling

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Word count: 6800 excluding references Number of references: 113Number of greyscale and color illustrations: 7 greyscale and 5 color (online only)Ghezzi 2 AbstractStudies of redox proteomics to identify glutathionylated proteins have so far been focused on intracellular proteins. However, plasma proteins have been described as glutathionylated. The present review discusses the redox state of protein cysteines in relation to their cellular distribution. We focus in particular on the redox state of proteins secreted under inflammatory conditions and that may act as soluble mediators (cytokines). We describe the various approaches used to detect secreted glutathionylated proteins, the only thiol modification studied so far in secreted proteins, and the specific problems presented in the study of the secretome. This review will deal with a particular aspect of redox proteomics, the analysis of secreted proteins and their possible function. Ghezzi 3 Redox state of proteins in the context of their localization Redox proteomics of the thiol proteomeAccording to the Oxford English Dictionary, proteomics is "the study or analysis of the set of proteins expressed by an organism" and we commonly apply the term to high-throughput techniques of protein identification. As such, the history of redox proteomics started in 2002 when various groups published the first reports of the identification of oxidized proteins by modifying the existing proteomic techniques.Two of these papers were aimed at carbonylated proteins (19,20) and others at protein glutathionylation (33,37,61) or overall protein thiol oxidation (60) .This review will deal with the redox states of protein thiols. Biochemistry textbooks and protein databases classify cysteines in proteins as either free or engaged in a disulfide bond. However, "free" cysteines can be reversibly or irreversibly oxidized to various forms. In particular, in addition to forming structural disulfides, cysteines can form transient, reversible disulfides with another protein cysteine, with free cysteine (cysteinylation) or with the cysteine in the tripeptide glutathione (GSH;; glutamylcystenyl-glycine). Fig. 1 lists the most important oxidation state of sulfur in cysteine.These forms of oxidation, due to their reversibility, are of great interest in the context of redox regulation, as a means by which the redox state of the cell can regulate protein functions (43-45).Specific proteins undergoing glutathionylation were described even before the term "proteomics" became popular (in the late 1990s, according to Google books ngram viewer -https://books.google.com/ngrams). Two proteins have been identified as undergoing glutathionylation in two separate papers, an unidentified 30 kDa cytosolic Ghezzi 4protein in oxidant-treated rat liver (79), and actin in human neutrophils during oxidative burst (22). Although these were not the result of high-throughput studies, some of the technologies used were then adapted for two-dimensional gels for further studies and are at the basis of current red...

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“…Thambisetty and Lovestone discovered that the plasma concentration of clusterin is associated with disease severity, pathology, and clinical progression in AD, as well as with brain fibrillar A burden in nondemented older individuals [94]. Studies form our group demonstrated that haptoglobin, one of the most abundantly secreted glycoproteins with chaperone function, was found to be either increasingly downregulated or increasingly oxidized in plasma from AD and MCI patients compared with controls [95]. We also demonstrated that in vitro oxidation of haptoglobin affects the formation of amyloid-fibrils, thus suggesting that oxidized haptoglobin is not able to act as an extracellular chaperone to prevent or slow formation of amyloid-aggregates.…”

Section: Advances In Geriatricsmentioning

confidence: 82%

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

Domenico

Head

Butterfield

et al. 2014

Advances in Geriatrics

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Free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases, because in the majority of cases it is a non-reversible phenomenon that requires clearance systems for removal. Major consequences of protein oxidation are loss of protein function and the formation of large protein aggregates, which are often toxic to cells if allowed to accumulate. Deposition of aggregated, misfolded, and oxidized proteins may also result from the impairment of protein quality control (PQC) system, including protein unfolded response, proteasome, and autophagy. Perturbations of such components of the proteostasis network that provides a critical protective role against stress conditions are emerging as relevant factor in triggering neuronal death. In this outlook paper, we discuss the role of protein oxidation as a major contributing factor for the impairment of the PQC regulating protein folding, surveillance, and degradation. Recent studies from our group and from others aim to better understand the link between Down syndrome and Alzheimer's disease neuropathology. We propose oxidative stress and alteration of proteostasis network as a possible unifying mechanism triggering neurodegeneration.

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Decreased expression and increased oxidation of plasma haptoglobin in Alzheimer disease: Insights from redox proteomics

Cited by 60 publications

References 52 publications

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Redox Proteomics Applied to the Thiol Secretome

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

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Decreased expression and increased oxidation of plasma haptoglobin in Alzheimer disease: Insights from redox proteomics

Cited by 60 publications

References 52 publications

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Redox Proteomics Applied to the Thiol Secretome

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

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Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin