The role of protein-thiol mixed disulfides in cataractogenesis

Lou, Marjorie F.; Dickerson, Jaime E.; Garadi, Rekha

doi:10.1016/0014-4835(90)90133-f

Cited by 75 publications

(52 citation statements)

References 9 publications

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“…Depletion of GSH in early postnatal mice causes cell damage to epithelial and fiber cells (70,89), an effect that can be prevented by pretreatment with glutathione ester (89). Mixed protein-thiol and protein-protein disulfide bonds have been reported in lens proteins (23,82,83,181). Because the formation of disulfide bonds precedes the characteristic morphological changes of cataracts, it has been proposed BERTHOUD AND BEYER 340…”

Section: Contribution Of Oxidative Stress To Cataract Formationmentioning

confidence: 99%

Oxidative Stress, Lens Gap Junctions, and Cataracts

Berthoud

Beyer

2009

Antioxidants & Redox Signaling

217

141

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The eye lens is constantly subjected to oxidative stress from radiation and other sources. The lens has several mechanisms to protect its components from oxidative stress and to maintain its redox state, including enzymatic pathways and high concentrations of ascorbate and reduced glutathione. With aging, accumulation of oxidized lens components and decreased efficiency of repair mechanisms can contribute to the development of lens opacities or cataracts. Maintenance of transparency and homeostasis of the avascular lens depend on an extensive network of gap junctions. Communication through gap junction channels allows intercellular passage of molecules (up to 1 kDa) including antioxidants. Lens gap junctions and their constituent proteins, connexins (Cx43, Cx46, and Cx50), are also subject to the effects of oxidative stress. These observations suggest that oxidative stress-induced damage to connexins (and consequent altered intercellular communication) may contribute to cataract formation. Antioxid. Redox Signal. 11, 339-353. 339The Eye Lens

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Section: Contribution Of Oxidative Stress To Cataract Formationmentioning

confidence: 99%

Oxidative Stress, Lens Gap Junctions, and Cataracts

Berthoud

Beyer

2009

Antioxidants & Redox Signaling

217

141

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“…Depletion of GSH and a concomitant increase of protein-thiol mixed disulfides during aging have been reported earlier (23,27). In vitro induction of mixed disulfide formation in young human and calf ␣-crystallin via incubation with GSSG, showed a direct effect of mixed disulfides on chaperone activity (Figs.…”

Section: Loss Of Chaperone-like Function Of ␣-Crystallin By Mixed Dismentioning

confidence: 99%

“…Lou et al (23) have reported two or more species of mixed disulfides in the human lens. The two major species of thiols bound to proteins are glutathione (PSSG) and cysteine (PSSC).…”

Section: Loss Of Chaperone-like Function Of ␣-Crystallin By Mixed Dismentioning

confidence: 99%

“…The ocular lens is under constant oxidative stress. In most types of cataracts, the common factor appears to be depletion of glutathione (GSH 1 ), presumably through the formation of oxidized glutathione (GSSG), which in turn forms protein-glutathione mixed disulfides (PSSG) (23,24,26,27). Human lenses exposed to oxidative stress have elevated levels of PSSG (27), a precursor of protein disulfides.…”

mentioning

confidence: 99%

“…␣-Crystallin has been shown to have such a chaperone-like function and is known to form a stable complex with denatured or partially unfolded proteins, preventing further aggregation (14 -17). During aging and cataractogenesis of the lens, both subunits of ␣-crystallin undergo extensive post-translational modifications such as deamidation (18,19), isomerization, racemization (20), oxidation (21), intramolecular disulfide bond formation (22), mixed disulfide formation (23,24), and glycation (25). The ocular lens is under constant oxidative stress.…”

mentioning

confidence: 99%

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Influence of Protein-Glutathione Mixed Disulfide on the Chaperone-like Function of α-Crystallin

Cherian

Smith

Jiang

et al. 1997

Journal of Biological Chemistry

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In an earlier report we showed that incubation of ␣-crystallin with oxidized glutathione results in significant loss of its chaperone-like activity. In the present study, we determined the effect of protein-glutathione mixed disulfides (PSSG), formed at Cys-131 in bovine ␣A-crystallin, and Cys-131 and Cys-142 in human ␣A-crystallin, on the function of ␣-crystallin as a molecular chaperone. After incubation of calf and young human ␣ L -crystallin fractions with oxidized glutathione, levels of PSSG were determined by performic acid oxidation of the mixed disulfides followed by reversed-phase high pressure liquid chromatography separation of phenylisothiocyanate-derivatized glutathione sulfonic acid. Levels of PSSG increased from 0.01 to 0.14 nmol/nmol (20 kDa) in bovine ␣ L -crystallin and from 0.022 to 0.25 nmol/ nmol in human ␣ L -crystallin. The presence of glutathione adducts at Cys-131 and Cys-142 were confirmed by mass spectral analysis. The chaperone-like activity was determined by the heat denaturation assay using ␤ Lcrystallin as the target protein. To examine the reversibility of the effect of mixed disulfides on chaperone activity, studies were done before and after reduction with the glutathione reductase system. Increased levels of PSSG resulted in lower chaperone activities. Treatment with the glutathione reductase system led to 80% reduction in PSSG levels with a concomitant recovery of the chaperone activity. These results suggest that cysteine(s) in the ␣A-crystallin subunit play an important role in the function of ␣-crystallin as a molecular chaperone.

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Lead‐induced oxidative stress and hematological alterations and their response to combined administration of calcium disodium EDTA with a thiol chelator in rats

Saxena

Flora

2004

J Biochem & Molecular Tox

103

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The therapeutic efficacy of calcium disodium ethylenediaminetetracetic acid (CaNa(2)EDTA) and the two thiol chelators, 2,3-dimercaptopropane 1-sulfonate (DMPS) and monoisoamyl dimercaptosuccinic acid (MiADMSA) was studied, both individually and in combination, in reducing lead concentration in blood and soft tissues and in restoring lead induced altered biochemical variables in rats. Exposure to subacute dose of lead implicated a critical role of reactive oxygen species (ROS) and oxidative stress in altering the normal values of these variables. Exposure to lead caused a significant inhibition of blood delta-aminolevulinic acid dehydratase (ALAD), an important enzyme in the haem synthesis pathway and glutathione (GSH) level. These changes were also accompanied by inhibition of ALAD activity in kidney, delta-aminolevulinic acid synthase (ALAS) activities in liver and changes in platelet counts in whole blood suggesting disturbed haem synthesis pathway. Lead exposure also led to a pronounced depletion of brain GSH contents, superoxide dismutase (SOD) activity, an increase in thiobarbituric acid reactive substances (TBARS), and activity of glutathione S-transferase (GST). Specific activities of membrane-bound enzymes, acetylcholinesterase (AChE) and monoamine oxidase (MAO), were significantly inhibited on lead exposure. These biochemical changes were correlated with increased uptake of lead in blood and soft tissues. Post lead exposure treatment with MiADMSA in particular provided significant recovery in altered biochemical variables besides significant depletion of tissue lead burden. Treatment with CaNa(2)EDTA and DMPS individually had only moderate beneficial effects on tissue oxidative stress, although they were equally effective in the removal of tissue lead burden. Tissue zinc and copper levels did not depict any significant depletion, although changes like marked depletion of zinc following CaNa(2)EDTA and copper after MiADMSA administration were of some concern. Combined administration of CaNa(2)EDTA, particularly with MiADMSA, was the most effective treatment protocol compared to all other treatments. It can be concluded from our present results that combined therapy with CaNa(2)EDTA and MiADMSA proved significantly better in restoring biochemical and clinical variables over monotherapy with these chelating agents against subacute lead exposure in adult rats.

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The role of protein-thiol mixed disulfides in cataractogenesis

Cited by 75 publications

References 9 publications

Oxidative Stress, Lens Gap Junctions, and Cataracts

Oxidative Stress, Lens Gap Junctions, and Cataracts

Influence of Protein-Glutathione Mixed Disulfide on the Chaperone-like Function of α-Crystallin

Lead‐induced oxidative stress and hematological alterations and their response to combined administration of calcium disodium EDTA with a thiol chelator in rats

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