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Tadao Maeda, Kiichiro Okano, Yu Chen, Vishal Chauhan, Grazyna Palczewska, Akiko Maeda, Krzysztof Palczewski; Unique Photoreceptor Cell Death Profile In All-trans-retinal-associated Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):953.
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To study the pathological functions of cone and rod photoreceptor cells in light-induced retinal degeneration associated with accumulation of toxic all-trans-retinal and its associated condensation products such as diretinoid-pyridinium-ethanolamine (A2E).
We prepared light-induced retinal degeneration mouse models with rod-rich or cone-rich retina by genetically ablating with cone-DTA (cone-specific diphtheria toxin A) transgene or deletion of Nrl (rod photoreceptor-specific neural retina leucine zipper protein gene) in a Rdh8-/-Abca4-/-mouse background, in which clearance of all-trans-retinal is impaired, to examine the contribution of rods and cones to light-induced photoreceptor degeneration under different light conditions. Morphological changes in the retina were evaluated by histological techniques and in vivo ophthalmological imaging systems (scanning laser ophthalmoscope: SLO, spectral domain-optical coherence tomography: SD-OCT). Physiological and biochemical functions in the retina were investigated by electroretinography (ERG) and retinoid analysis.
Nrl-/-Rdh8-/-Abca4-/-(cone-rich) and cone-DTARdh8-/-Abca4-/- (rod-rich) retinas showed much milder degeneration compared with Rdh8-/-Abca4-/- retina (cone and rod) under a regular light cycle at 3 months of age. Although these three mouse models displayed progression in their retinal degeneration by the age of 6 months, cone-DTARdh8-/-Abca4-/- retina showed slower progression than Nrl-/-Rdh8-/-Abca4-/-and Rdh8-/-Abca4-/- retinas. After intense light exposure, photoreceptors in cone-DTA Rdh8-/-Abca4-/- and Rdh8-/-Abca4-/- retinas were severely degenerated whereas no significant photoreceptor cell death was observed in Nrl-/-Rdh8-/-Abca4-/- retina. Different amounts of A2E were detected in these animals.
Progression of retinal degeneration induced by delayed clearance of all-trans-retinal was affected by the population density of rod and cone photoreceptors. This suggests that macular-specific distribution of cone/rod cells may dictate the characteristic photoreceptor degeneration observed in human age-related macular degeneration.
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