June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Mouse deficiency with both gamma glutamate-cysteine ligase catalytic subunit (Gclc) and modifier subunit (Gclm) develops an early nuclear cataract
Author Affiliations & Notes
  • Zongbo WEI
    Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
  • Caili Hao
    Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
  • Vincent M Monnier
    Department of Pathology and Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States
  • Xingjun Fan
    Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Zongbo WEI None; Caili Hao None; Vincent Monnier None; Xingjun Fan None
  • Footnotes
    Support  NEI EY028158(XF) P30EY031631
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1945. doi:
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      Zongbo WEI, Caili Hao, Vincent M Monnier, Xingjun Fan; Mouse deficiency with both gamma glutamate-cysteine ligase catalytic subunit (Gclc) and modifier subunit (Gclm) develops an early nuclear cataract. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1945.

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

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Abstract

Purpose : Glutathione (GSH) is the most abundant anti-oxidative compound of the lens. In age-related nuclear cataracts (ARNC), GSH levels are impaired and accompanied by increased protein oxidation, disulfide formation, and cross-linking. We found ARNC formation (4-12mos) in the LEGSKO mouse in which lenticular GSH levels were conditionally knocked out by targeting the gamma glutamate-cysteine ligase catalytic subunit (Gclc) on FVB/B6 hybrid genetic background. However, no ARNC was seen when we bred LEGSKO mice to a C57BL/6 genetic background. To gain insight into GSH homeostasis and cataractogenesis, we compared LEGSKO, modifier subunit (Gclm) KO, and double-knockout (DKO, Gclc/Gclm) mice all on C57BL/6 genetic background.

Methods : Lens cataracts were monitored by a slit-lamp up to 12mos. Lens morphology and transparency were further confirmed with darkfield microscopy and histology staining. Lens glutathione, protein disulfide, protein glutathionylation, glutathione reductase and GAPDH activity, and protein aggregation were measured.

Results : We did not observe significant nuclear cataract formation up to 12-month-old in LEGSKO and Gclm KO mice. However, severe nuclear cataracts were seen in DKO mice as early as 1-month-old. Interestingly, not all DKO mice developed cataracts in both eyes, and very few DKO mice did not develop cataracts in both eyes for up to 12-month-old. A comprehensive comparison of lens redox status, antioxidant enzyme activity, and protein sulfhydryl status between DKO, LEGSKO, Gclm KO, and WT mice offered the mechanisms of why DKO mice develop early nuclear cataracts.

Conclusions : We have established several accelerated lens aging models. Gclc/Gclm DKO mouse develops nuclear cataracts. The phenotypic heterogeneity of DKO mice may explain why some people never develop cataracts.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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