Light Damage inAbca4andRpe65rd12Mice

Li, Wu; Ueda, Keiko; Nagasaki, Taka; Sparrow, Janet R.

doi:10.1167/iovs.14-13867

Cited by 37 publications

(44 citation statements)

References 74 publications

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“…We have previously shown that Abca4 −/− mice burdened with increased bisretinoid are more susceptible to retinal light damage than are wild-type mice (31). Older mice carrying greater levels of bisretinoid are also more susceptible than younger mice, and light damage was not observed in Rpe65 rd12 mice that carry little or no RPE bisretinoid.…”

Section: Discussionmentioning

confidence: 96%

“…Three histological sections through the optic nerve head were analyzed (31). ONL area was calculated as the sum of the ONL thicknesses in superior and inferior retina (0.2-2.…”

Section: Discussionmentioning

confidence: 99%

“…4C). Importantly, the thinning of ONL that is indicative of reduced photoreceptor cell viability in albino Abca4 −/− mice (15,16,31) was less pronounced in the vitamin E-treated mice (Fig. 4D).…”

Section: Accumulation Of Bisretinoid In Dark-and Light-reared Albino mentioning

confidence: 96%

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Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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111

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

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Section: Discussionmentioning

confidence: 96%

“…Three histological sections through the optic nerve head were analyzed (31). ONL area was calculated as the sum of the ONL thicknesses in superior and inferior retina (0.2-2.…”

Section: Discussionmentioning

confidence: 99%

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Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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111

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“…Ueda et al [55] showed that ABCA4 −/− animals were more susceptible to light damage than WT animals and that in both groups, older animals carrying larger amounts of LBs were also more susceptible. More recently Ref.…”

Section: Phototoxicitymentioning

confidence: 99%

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Nociari¹,

Kiss²,

Rodríguez-Boulan³

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

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Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

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“…A1120 has been reported before in this mechanistic context [7], but this had not been applied to the treatment dry AMD or Stargardt Disease. In the Abca4(-/-) mouse future science group Patent Highlights Mucke model that manifests accelerated accumulation of lipofuscin in the retinal pigment epithelium [8], the levels of A2E and other bisretinoids were reduced by approximately 50%. The widely expressed transmembrane proteins of the 'A Disintegrin And Metalloprotease' (ADAM) class are also known as 'sheddases' because their intrinsically disordered extracellular domains can induce shedding of many important cell surface proteins resulting in the release of biologically active soluble factors; they also act as integrin ligands [9].…”

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confidence: 99%