Abstract
Age-related nuclear cataracts are associated with progressive post-synthetic modifications of crystallins from various physical chemical and metabolic insults, of which oxidative stress is a major factor. The latter is normally suppressed by high concentrations of glutathione (GSH), which however are very low in the nucleus of the old lens. Here we generated a mouse model of oxidant stress by knocking out glutathione synthesis in the mouse in the hope of recapitulating some of the changes observed in human age-related nuclear cataract (ARNC). A floxed Gclc mouse was generated and crossed with a transgenic mouse expressing Cre in the lens to generate the LEGSKO mouse in which de novo GSH synthesis was completely abolished in the lens. Lens GSH levels were reduced up to 60% in homozygous LEGSKO mice, and a decreasing GSH gradient was noticed from cortical to nuclear region at 4 months of age. Oxidation of crystallin methionine and sulfhydryls into sulfoxides was dramatically increased, but methylglyoxal hydroimidazolones levels that are GSH/glyoxalase dependent were surprisingly normal. Homozygous LEGSKO mice developed nuclear opacities starting at 4 months that progressed into severe nuclear cataract by 9 months. We conclude that the LEGSKO mouse lens mimics several features of human ARNC and is thus expected to be a useful model for the development of anti-cataract agents.
Highlights
Cataract is a leading cause of blindness, accounting for 50% of blindness worldwide [1]
No lens abnormalities have been reported for mice that are hemizygous or homozygous for the MRL10-cre transgene in the absence of floxed alleles [17], and phenotypes manifested in Lens Glutathione Synthesis KnockOut (LEGSKO) mice were contributed by Gclc deficiency alone
The LEGSKO mice were continuously crossbred with Gclcfl/fl mice (C57BL/6) to convert the genomic background towards C57BL/6
Summary
Cataract is a leading cause of blindness, accounting for 50% of blindness worldwide [1]. Surgical removal of the cataractous lens remains the only therapy, yet the National Eye Institute has estimated that a ten-year delay in the onset of cataract would result in a 50% reduction in the prevalence of cataract [3]. Major age-related lens protein modifications include deamidation, deamination, racemization, accumulation of truncation products, accumulation of UV active, fluorescent, and non-UV active protein adducts and crosslinks from glycation, ascorbylation and lipoxidation reactions [5]. These modifications contribute toward decreasing protein stability, partly by impairing the chaperone function of acrystallins, the levels of which decrease with age due to insolubilization [6]. While oxidative damage is subdued during normal aging, it is a major cause or consequence of nuclear cataracts, the most common types of age-related cataracts, whereby the loss of glutathione (GSH) and formation of disulfides are considered to be the key factors in oxidative stress and nuclear cataractogenesis [7]
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