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Sidney M. Gospe, III, Luyu Wang, Mikael Klingeborn, Amanda Travis, Ying Hao, Vadim Y Arshavsky; Progressive Optic Atrophy in a Retinal Ganglion Cell-Specific Mouse Model of Complex I Deficiency. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3957.
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To generate and characterize a mouse model of mitochondrial optic neuropathy via retinal ganglion cell (RGC)-specific deletion of the complex I subunit NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4).
A transgenic mouse line expressing Cre recombinase under transcriptional control of the promoter for the vesicular glutamate transporter Vglut2 (Vglut2-Cre) was crossed with a Cre-dependent tdTomato reporter line, and the expression of Cre was assessed in retinal cross-sections and flat mounts. The Vglut2-Cre;ndufs4loxP/loxP transgenic mouse line was then generated to delete ndufs4 within most RGCs. Optic nerve NDUFS4 protein content was determined via Western blot, and the retinal phenotype was assessed via electroretinography and histological quantification of RGC somas in retinal flat mounts and RGC axon density within optic nerve cross-sections at multiple time points.
Vglut2-driven Cre expression was achieved in 96% of RGCs, but also in a small fraction of cones and horizontal cells. Inactivation of ndufs4 in RGCs resulted in reduced expression of NDUFS4 protein within the optic nerves of Vglut2-Cre;ndufs4loxP/loxP mice. No significant outer retinal electrophysiological abnormalities were detected, whereas degeneration of RGCs in Vglut2-Cre;ndufs4loxP/loxP retinas commenced around postnatal day 45 (P45) and progressed to loss of two-thirds of RGCs by P90. Abnormal RGC axon myelination was observed on electron microscopy in the optic nerves of mutant mice.
Complex I deficiency achieved via cell-specific deletion of ndufs4 in RGCs induces profound optic atrophy within 3 months. Compared to the germline ndufs4-/- knockout mouse, the longer lifespan of the Vglut2-Cre;ndufs4loxP/loxP mouse makes this transgenic line a promising preclinical model for testing therapies for mitochondrial optic neuropathies such as Leber Hereditary Optic Neuropathy.
This is a 2020 ARVO Annual Meeting abstract.
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