June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Proteomic changes in the lens of a congenital cataract mouse model lead to reduced levels of glutathione and taurine
Author Affiliations & Notes
  • Sheldon Rowan
    Laboratory of Nutrition and Vision Research, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts, United States
    Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States
  • Eloy Bejarano
    Envejecimiento celular y nutrición, CEU Universidad Cardenal Herrera, Moncada, Comunitat Valenciana, Spain
  • Elizabeth A Whitcomb
    Laboratory of Nutrition and Vision Research, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts, United States
  • Rebecca L Pfeiffer
    Moran Eye Center, The University of Utah School of Medicine, Salt Lake City, Utah, United States
  • Kristie L Rose
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
  • Kevin L Schey
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
  • Bryan W. Jones
    Moran Eye Center, The University of Utah School of Medicine, Salt Lake City, Utah, United States
  • Allen Taylor
    Laboratory of Nutrition and Vision Research, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts, United States
    Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Sheldon Rowan None; Eloy Bejarano None; Elizabeth Whitcomb None; Rebecca Pfeiffer None; Kristie Rose None; Kevin Schey None; Bryan Jones None; Allen Taylor None
  • Footnotes
    Support  NIH RO1EY028559, RO1EY026979, USDA 8050-51000-089-01S (to A.T.) This material is based upon work supported by the US Department of Agriculture-Agricultural Research Service (ARS), under Agreement No. 58-8050-9-004; No. 58-8050-9-003
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4038 – F0002. doi:
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    • Get Citation

      Sheldon Rowan, Eloy Bejarano, Elizabeth A Whitcomb, Rebecca L Pfeiffer, Kristie L Rose, Kevin L Schey, Bryan W. Jones, Allen Taylor; Proteomic changes in the lens of a congenital cataract mouse model lead to reduced levels of glutathione and taurine. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4038 – F0002.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Congenital cataracts develop through multiple mechanisms, but often lead to common endpoints, including protein aggregation, impaired fiber cell differentiation, and absence of fiber cell denucleation. It is now apparent that other metabolic abnormalities associate with cataractogenesis, including reductions in levels of amino acids, glutathione, and taurine. Here, we analyze the proteome and metabolome of mice expressing a mutant ubiquitin protein (K6W-Ub) to determine the molecular mechanisms underlying formation of its congenital cataract.

Methods : C57BL/6J wild-type or cataractous K6W-Ub transgenic mouse lenses were dissected at E15.5, P1, or P30 and proteins were analyzed via MS-based tandem-mass-tag (TMT) quantitative proteomics. Small molecules were spatially quantified using computational molecular phenotyping (CMP), a tool that enables acquisition of free amino acid fingerprints for every cell in the lens. Validation of proteomics findings was also performed using Western blot analysis and immunohistochemistry.

Results : Proteomic analyses revealed pathways that were altered during lens differentiation, by expression of K6W-Ub, or both. Prominent pathways included glutathione metabolism; glycolysis/gluconeogenesis; and glycine, serine, and threonine metabolism. Within the glutathione metabolism pathway, GSTP1 and GGCT were most strongly downregulated by K6W-Ub. Other consistently downregulated proteins were PGAM2, GAMT, and HMOX1. Proteins that were upregulated by K6W-Ub expression belonged to pathways related to lysosome, autophagy, Alzheimer’s disease, and glycolysis/gluconeogenesis. Analysis of the metabolome via CMP revealed statistically significant decreases in taurine and glutathione and smaller decreases in glutamate, glutamine, aspartate, and valine in all ages of K6W-Ub lenses. Lens metabolites were spatially altered in the cataractous K6W-Ub lens.

Conclusions : K6W-Ub expressing lenses replicate many congenital cataract phenotypes and are useful disease models. The large reductions in levels of taurine and glutathione may be general signatures of cataract development, as human cataracts also have reduced glutathione and taurine. Key roles for amino acid metabolism and glycolysis/gluconeogenesis in cataractogenesis are emerging. Together our data point toward potential common metabolic/proteomic signatures of cataracts.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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