Ultraviolet Radiation–Induced Cataract in Mice: The Effect of Age and the Potential Biochemical Mechanism

Zhang, Jie; Zhang, Pengcheng; Löfgren, Stefan; Tian, Xiao-Li; Lou, Marjorie F.

doi:10.1167/iovs.12-10482

Cited by 53 publications

(46 citation statements)

References 52 publications

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“…Age-onset cataract is a highly prevalent disease as well as a case study in protein aging. Its pathology has multiple contributing factors, including exposure to UV light, tobacco, and certain specific chemicals; however, the effect is generally the sameaggregation of the eye lens crystallins (5,13,16,17,60,61). In line with the multiple causality of the disease, several distinct biochemical perturbations in vitro have been shown to cause crystallin aggregation (54,(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin

Serebryany

Woodard

Adkar

et al. 2016

Journal of Biological Chemistry

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Considerable mechanistic insight has been gained into amyloid aggregation; however, a large number of non-amyloid protein aggregates are considered "amorphous," and in most cases, little is known about their mechanisms. Amorphous aggregation of ␥-crystallins in the eye lens causes cataract, a widespread disease of aging. We combined simulations and experiments to study the mechanism of aggregation of two ␥D-crystallin mutants, W42R and W42Q: the former a congenital cataract mutation, and the latter a mimic of age-related oxidative damage. We found that formation of an internal disulfide was necessary and sufficient for aggregation under physiological conditions. Two-chain all-atom simulations predicted that one non-native disulfide in particular, between Cys 32 and Cys 41 , was likely to stabilize an unfolding intermediate prone to intermolecular interactions. Mass spectrometry and mutagenesis experiments confirmed the presence of this bond in the aggregates and its necessity for oxidative aggregation under physiological conditions in vitro. Mining the simulation data linked formation of this disulfide to extrusion of the N-terminal ␤-hairpin and rearrangement of the native ␤-sheet topology. Specific binding between the extruded hairpin and a distal ␤-sheet, in an intermolecular chain reaction similar to domain swapping, is the most probable mechanism of aggregate propagation.

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Section: Discussionmentioning

confidence: 99%

An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin

Serebryany

Woodard

Adkar

et al. 2016

Journal of Biological Chemistry

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show abstract

“…Its pathology has multiple contributing factors, including exposure to UV light, tobacco, and certain specific chemicals; however, the effect is generally the sameaggregation of the eye lens crystallins (5,13,16,17,60,61). In line with the multiple causality of the disease, several distinct biochemical perturbations in vitro have been shown to cause crystallin aggregation (54,(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

Serebryany

Woodard

Adkar

et al. 2017

Biophysical Journal

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Considerable mechanistic insight has been gained into amyloid aggregation; however, a large class of non-amyloid protein aggregates are considered "amorphous," and in most cases little is known about their mechanisms. Amorphous aggregation of γ-crystallins in the eye lens causes a widespread disease of aging, cataract. We combined simulations and experiments to study the mechanism of aggregation of two γD-crystallin mutants, W42R and W42Q -the former a congenital cataract mutation, and the latter a mimic of age-related oxidative damage. We found that formation of an internal disulfide was necessary and sufficient for aggregation under physiological conditions. Twochain all-atom simulations predicted that one nonnative disulfide in particular, between Cys32 and Cys41, was likely to stabilize an unfolding intermediate prone to intermolecular interactions. Mass spectrometry and mutagenesis experiments confirmed the presence of this bond in the aggregates and its necessity for oxidative aggregation under physiological conditions in vitro. Mining the simulation data linked formation of this disulfide to extrusion of the N-terminal β-hairpin and rearrangement of the native β-sheet topology.

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“…Previous studies have proved that lens is sensitive to radiation such as X‐ray (Pendergrass et al, ), UV light (Zhang et al, ), and low‐power microwave radiation [5]. Because it is nonvascularized and noninnervated and contains a high percentage of water, lens has a relatively high absorption rate when exposed to radiation.…”

Section: Discussionmentioning

confidence: 99%

Extremely Low Frequency Magnetic Fields Do Not Induce DNA Damage in Human Lens Epithelial Cells In Vitro

Zhu

Qian³

et al. 2016

The Anatomical Record

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Non-ionizing radiations, e.g., radiofrequency electromagnetic fields, could induce DNA damage and oxidative stress in human lens epithelial cells (LECs) which can be early events in cataractogenesis. Extremely low frequency magnetic fields (ELF MF) as another common form of manmade electromagnetic fields has been considered as suspected human carcinogen by International Agency for Research on Cancer (IARC) and become a focus that people play more and more attentions to. This study aimed to determine whether ELF MF can induce DNA damage in cultured human LECs at a relatively low intensity. Human LECs were exposed or sham-exposed to a 50 Hz ELF MF which produced by a well-designed exposure system at the intensity of 0.4 mT. DNA damage in human LECs was examined by the phosphorylated form of histone variant H2AX (gH2AX) foci formation assay and further explored with western blot, flow cytometry, and alkaline comet assay. Immunofluorescence analysis showed that 0.4 mT ELF MF did not significantly increase gH2AX foci formation in human LECs after 2, 6, 12, 24, or 48 hr exposure. No significant differences had been detected in gH2AX expression level between the ELF MFand sham-exposure groups, while no obvious chromosomal DNA fragmentation was detected by alkaline comet assay after ELF MF exposure. The results indicate an absence of genotoxicity in ELF MF-exposed human epithelial cells and do not support the hypothesis that environmental ELF MF might be causally led to genomic instability via chromosomal damage response processes. Neither short nor long term continuous exposure to 50 Hz ELF MF at 0.4 mT could induce DNA damage in human lens epithelial cells in vitro. Anat Rec, 299:688-697,

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Ultraviolet Radiation–Induced Cataract in Mice: The Effect of Age and the Potential Biochemical Mechanism

Cited by 53 publications

References 52 publications

An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin

An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin

An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

Extremely Low Frequency Magnetic Fields Do Not Induce DNA Damage in Human Lens Epithelial Cells In Vitro

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