June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Longitudinal age effects of optineurin E50K mutation and deficiency on visual function
Author Affiliations & Notes
  • Vishnu Adi
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Jeffrey Sims
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Dominick Forlenza
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Crystal Liu
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Hana Song
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Giles Hamilton-Fletcher
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Nicole Colwell
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Muneeb A Faiq
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
  • Hiroshi Ishikawa
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
    Department of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, New York, United States
  • Gadi Wollstein
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
    Department of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, New York, United States
  • Joel S Schuman
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
    Department of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, New York, United States
  • Henry Tseng
    Duke University Department of Ophthalmology, Durham, North Carolina, United States
  • Kevin Chan
    Department of Ophthalmology, New York University School of Medicine, New York, New York, United States
    Department of Radiology, New York University School of Medicine, New York, New York, United States
  • Footnotes
    Commercial Relationships   Vishnu Adi, None; Jeffrey Sims, None; Dominick Forlenza, None; Crystal Liu, None; Hana Song, None; Giles Hamilton-Fletcher, None; Nicole Colwell, None; Muneeb Faiq, None; Hiroshi Ishikawa, None; Gadi Wollstein, None; Joel Schuman, Zeiss (P); Henry Tseng, Allergan (C); Kevin Chan, None
  • Footnotes
    Support  This work was supported in part by the National Institutes of Health R01-EY028125 and K08-EY021520 (Bethesda, Maryland); BrightFocus Foundation G2013077, G2016030, and G2019103 (Clarksburg, Maryland); Research to Prevent Blindness/Stavros Niarchos Foundation International Research Collaborators Award (New York, New York), American Glaucoma Society (San Francisco, California), Alcon Research Institute Young Investigator Award (Fort Worth, Texas), and unrestricted grants from Research to Prevent Blindness to NYU Langone Health Department of Ophthalmology and the Duke Eye Center (New York, New York).
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2385. doi:
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    • Get Citation

      Vishnu Adi, Jeffrey Sims, Dominick Forlenza, Crystal Liu, Hana Song, Giles Hamilton-Fletcher, Nicole Colwell, Muneeb A Faiq, Hiroshi Ishikawa, Gadi Wollstein, Joel S Schuman, Henry Tseng, Kevin Chan; Longitudinal age effects of optineurin E50K mutation and deficiency on visual function. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2385.

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

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Abstract

Purpose : Mutations in optineurin (OPTN) are associated with familial normal tension glaucoma and other neurodegenerative diseases. It remains unclear how OPTN loss or mutation alters visual function during aging. Here, we used transgenic mouse models and in vivo assessments to test the hypothesis that OPTN dysfunction contributes to progressive visual impairment through a toxic gain of function mechanism.

Methods : Mice with C57BL/6 background were used (Fig 1): wildtype (WT; n=19), homozygous OPTN knock-out (mOPTN-KO; n=13), hemizygous mouse E50K OPTN knock-in (mE50K-het; n=8), homozygous mouse E50K OPTN knock-in (mE50K homoz; n=10), and human E50K OPTN bacterial artificial chromosome overexpression (hE50K BAC; n=6) (PMID: 31076632, 25818176). Intraocular pressure (IOP), total retinal thickness (TRT), visual acuity (VA), and contrast sensitivity (CS) were measured at 6, 12, and 18 months of age in the same mice using the TonoLab rebound tonometer, Bioptigen spectral-domain optical coherence tomography imaging, and OptoMotry optokinetic virtual reality system, respectively. Left and right eye data were averaged and analyzed using ANOVAs followed by posthoc tests between genotype and age groups, as well as linear regressions for VA versus contrast threshold (CT).

Results : Our longitudinal study of the same mice during the aging process showed that IOP remained normal between 10-15 mmHg (Fig 2A). Small to no difference in TRT over time or compared to WT was observed (Fig 2B). mE50K-homoz, mE50K-het, and hE50K BAC mice exhibited greater age-dependent decline in VA and CT than WT or mOPTN-KO mice (Fig 2C, 2D, 2E). In contrast, mOPTN-KO mice showed preservation of VA and CT over time compared to WT. Consistently, mice with one copy of E50K OPTN (mE50K het) experienced less deterioration of VA and CT compared to mice with two copies (mE50K homoz) or mild overexpression (hE50K BAC).

Conclusions : Depsite limited IOP and TRT changes between age and genotype groups, E50K OPTN was associated with differential age-dependent visual impairment (greater for CS than VA). Surprisingly, OPTN deficiency preserved visual function such that CS in knockout mice was better than WT mice. Our results suggest visual loss associated with E50K OPTN is due to a toxic gain of function mechanism, and that suppression of OPTN might constitute a therapeutic strategy for glaucomatous neurodegeneration.

This is a 2021 ARVO Annual Meeting abstract.

 

 

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