Unbalanced redox status network as an early pathological even in congenital cataracts

Abstract

Aims/Purpose: The lens proteome undergoes dramatic composition changes during development and maturation. Defective developmental processes lead to congenital cataracts that account for about 30% of cases of childhood blindness. Gene mutations are associated with approximately 50% of early‐onset forms of lens opacity, with the remainder being of unknown aetiology. To gain a better understanding of congenital cataractogenesis, we utilized a transgenic mouse model expressing a mutant ubiquitin protein in the lens (K6W‐Ub) that recapitulates many of the early pathological changes seen in human congenital cataracts.Methods: We performed MS‐based tandem‐mass‐tag quantitative proteomics (TMT), computational molecular phenotyping (CMP), high‐performance liquid chromatography (HPLC), western blotting and immunohistochemical analysis in E15, P1 and P30 control or K6W‐Ub lenses.Results: TMT identified proteins that were altered during normal lens differentiation, some of which were also altered in cataractous lenses. These included proteins in glutathione and amino acid metabolic pathways. CMP revealed that glutathione and taurine were reduced spatially altered in the K6W‐Ub cataractous lens. HPLC revealed that both the ratio GSH/GSSG and taurine, two indicators of redox status, were differentially compromised in K6W‐Ub cataractous lenses.Conclusions: Our findings shed light on the molecular mechanisms associated with congenital cataracts and point out that unbalanced redox status due to reduced levels of taurine and glutathione, metabolites already linked to age‐related cataract, could be a major underlying mechanism behind lens opacities that appear early in life.Funding: Funding was provided by grants RYC 2018‐024434‐I, MINECO PID 2020‐119466RB‐I00, FUSP‐PPC‐19‐B53C4C64, NIH RO1EY026979 (to AT), USDA 8050‐51000‐089‐01S (to AT).