Cross-Linking of Lens Crystallins in a Photodynamic System: A Process Mediated by Singlet Oxygen

Goosey, JD; Zigler, J. Samuel; Kinoshita, Jin H.

doi:10.1126/science.7375939

Cited by 193 publications

(101 citation statements)

References 36 publications

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“…in the lens (40)(41)(42)(43). The core portion of the lens is devoid of cell organelles; the cells of the peripheral zone, which are rich in mitochondria, are of major metabolic and protective importance.…”

Section: Resultsmentioning

confidence: 99%

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Mårtensson

Steinherz

Jain

et al. 1989

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

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BiochemistryGlutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage [mitochondria/glutathione mono(glycyl) Contributed by Alton Meister, August 30, 1989 ABSTRACT Treatment of newborn rats and mice with buthionine sulfoximine, an inhibitor of glutathione synthesis, leads to development of cataracts, which are not prevented by treatment with glutathione, but they are prevented by treatment with glutathione monoester. Cataracts are associated with glutathione deficiency in the lens epithelium, which undergoes severe degeneration. The findings indicate that glutathione normally functions in the protection of the lens and lens epithelium against oxidative injury, suggesting that procedures that increase lens glutathione levels might be useful for prevention of other types of cataracts. Relatively low doses of buthionine sulfoximine produce cataracts in newborn animals, and treatment of pregnant mice with buthionine sulfoximine during the last part of gestation leads to cataract formation in the offspring. The high sensitivity of the developing lens to the effects of glutathione deficiency suggests that this tissue may be a useful model for studies on glutathione function.

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Section: Resultsmentioning

confidence: 99%

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Mårtensson

Steinherz

Jain

et al. 1989

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

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“…Several endogenous lens chromophores such as N-formylkynurenine, riboflavin, and age-related yellow compounds absorb light present in the environment and have the capacity to act as photosensitizers generating reactive oxygen species such as singlet oxygen (16). Singlet oxygen has been implicated in the cataractogenic process as a highly reactive species that can cross-link lens proteins and produce high molecular weight aggregates (17). When illuminated, rose bengal is a classic singlet oxygen generator (18).…”

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confidence: 99%

“…When illuminated, rose bengal is a classic singlet oxygen generator (18). The effects of singlet oxygen on lens crystallin structure and cross-linking have been relatively well studied (17,19,20).…”

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confidence: 99%

Cloning, Expression, and Chaperone-like Activity of Human αA-Crystallin

Andley

Mathur

Griest

et al. 1996

Journal of Biological Chemistry

152

136

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One of the major protein components of the ocular lens, ␣-crystallin, is composed of ␣A and ␣B chain subunits that have structural homology to the family of mammalian small heat shock proteins. Like other small heat shock proteins, ␣-crystallin subunits associate to form large oligomeric aggregates that express chaperone-like activity, as defined by the ability to suppress nonspecific aggregation of proteins destabilized by treatment with a variety of denaturants including heat, UV irradiation, and chemical modification. It has been proposed that age-related loss of sequences at the C terminus of the ␣A chain subunit may be a factor in the pathogenesis of cataract due to diminished capacity of the truncated crystallin to protect against nonspecific aggregation of lens proteins. To evaluate the functional consequences of ␣-crystallin modification, two mutant forms of ␣A subunits were prepared by site-directed mutagenesis. Like wild type (WT), aggregates of ϳ540 kDa were formed from a tryptophan-free ␣A mutant (W9F). When added in stoichiometric amounts, both WT and W9F subunits completely suppressed the heat-induced aggregation of aldose reductase. In contrast, subunits encoded by a truncation mutant in which the Cterminal 17 residues were deleted (R157STOP), despite having spectroscopic properties similar to WT, formed much larger aggregates with a marked reduction in chaperone-like activity. Similar results were observed when the chaperone-like activity was assessed through inhibition of ␥-crystallin aggregation induced by singlet oxygen. These results demonstrate that the structurally conservative substitution of Phe for Trp-9 has a negligible effect on the functional interaction of ␣A subunits, and that deletion of C-terminal sequences from the ␣A subunit results in substantial loss of chaperone-like activity, despite overall preservation of secondary structure.The major components of the mammalian lens fiber cells are the ␣-, ␤-, and ␥-crystallins, which constitute an estimated 35% wet weight of the lens. The crystallins contribute to the transparency and refractive power of the lens by short range interactions among themselves and cytoskeletal elements in a highly concentrated matrix (1-3). ␣-Crystallin is one of the most abundant of the crystallins in mature lens fiber cells. It is a M r ϳ0.6 -1.0 ϫ 10 6 complex composed of two structurally related subunits, designated ␣A and ␣B, which are encoded by genes localized to chromosomes 21 and 11, respectively (4, 5).

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“…Such a viscosity increase likely reflects cross linking reactions, mediated by singlet oxygen or secondary reactive radicals, similar to those observed in model and intracellular protein systems. [27][28][29][30] …”

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confidence: 99%