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R.A. Radu, N.L. Mata, A. Bagla, G.H. Travis; A2E Accumulation and Photoreceptor Degeneration in Pigmented and Albino abcr–/– Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3519.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Recessive Stargardt's disease (STGD) is an inherited form of macular degeneration caused by mutations in the ABCR gene. To investigate the molecular etiology of STGD and potentially to develop new treatments, we previously generated mice with a knockout mutation in abcr. The biochemical, morphological, and physiological phenotype in abcr –/– mice is strikingly similar to that in STGD patients, including accumulation of A2E. This accumulation is thought to play a critical role in the photoreceptor degeneration of STGD. Unfortunately, photoreceptor degeneration is very slow in abcr –/– mice, which renders this a useless parameter for monitoring potential treatment effects. In the current study, we attempted to accelerate A2E accumulation and photoreceptor degeneration in abcr –/– mice. Methods: We placed the abcr –/– mutation onto an albino background. These mice were exposed to cyclic illumination at 30 or 120 lux for one month. Retinas and retinal pigment epithelia from albino (BALB/c) and pigmented (129/SVEV) abcr –/– mice were homogenized, extracted with solvent and analyzed by HPLC to determine levels of A2E, 11–cis–retinaldehyde, all–trans–retinaldehyde, and all–trans–retinyl esters. Retinas from these animals were also examined by light microscopy to determine the rates of photoreceptor degeneration. Results: We observed no increase in the rates of A2E accumulation or photoreceptor degeneration in the albino abcr –/– mice at the higher light intensity. The rate of A2E accumulation in albino was similar to pigmented abcr –/– mice exposed to 30 lux cyclic illumination. However, 11–cis–retinaldehyde was dramatically lower while all–trans–retinaldehyde and all–trans–retinyl esters were higher in eyes from albino compared to pigmented abcr –/– mice. These differences confirm higher retinal illuminance in albino compared to pigmented eyes at the same level of ambient light. In another study we demonstrated 2-3 fold higher rates of A2E accumulation in pigmented abcr –/– mice raised under constant light at 350 lux. We are currently exposing pigmented abcr –/– mice to still higher levels of cyclic light. Conclusions: These results suggest that A2E accumulation in pigmented abcr –/– mice is responsive to levels of ambient light. High rates of A2E accumulation and accelerated photoreceptor degeneration may be achieved in pigmented abcr –/– mice raised under bright cyclic light. These results suggest further that the rate of A2E accumulation is less sensitive to retinal illuminance in albino abcr –/– mice. Reduced stability of A2E in albino RPE cells lacking melanosomes is a possible explanation.
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