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Henry Tseng, Zachary Johnson, Kendall Kruszewski, Marc Caron; Age-dependent decrease in retinal ganglion cells and mitophagy associated with loss of optineurin. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3715.
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© ARVO (1962-2015); The Authors (2016-present)
The optineurin (OPTN) gene has been associated with retinal ganglion cell (RGC) loss in normal-tension glaucoma. Recent in vitro findings have shown that optineurin plays a role in the autophagy pathway, specifically in the degradation of damage or senescent mitochondria (mitophagy). Using a floxed OPTN mouse generated in our laboratory, we tested the hypothesis that loss of the optineurin gene will alter autophagy/mitophagy functions in vivo and decrease RGC survival.
OPTN knockout (OPTN-/-) mice were generated using the Cre-loxP recombination system. We analyzed eye anatomy, intraocular pressure, retina histology, retinal ganglion cell survival, and protein expression levels for autophagy/mitophagy markers. Differences between young (2-3 months old) and aged (10 months or older) groups as well as between genotypes were compared.
Loss of OPTN did not increase intraocular pressure or alter gross eye anatomy. OPTN -/- retinas exhibited a significant decrease in inner plexiform layer (p<0.001, n=9 animals for each genotypes) and ganglion cell layer (p<0.05) than wildtype, littermate control mice. Immunostaining and quantitation with the RGC marker RBPMS revealed less RGCs in young (n=6, p<0.05) and aged (n=3, p<0.001) OPTN-/- retinas. However, this loss was less in OPTN-/- retinas was less when RGC quantitation was performed with a neurofilament marker. No qualitative differences in other non-RGC retinal cell types were observed. An analysis of select autophagy and mitophagy markers in vivo revealed lower prohibitin2 (PHB2) expression, a marker of mitophagy, in aged OPTN -/- retinas.
Loss of optineurin function resulted in mild, age-dependent RGC loss and change in mitophagy function, but not eye anatomy or intraocular pressure. Further work using our optineurin mice will help elucidate how a disruption in optineurin function leads to neurodegeneration in the retina and the brain.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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