Evidence for two apoptotic pathways in light-induced retinal degeneration

Hao, Wenshan; Wenzel, Andreas; Obin, Martin S.; Chen, Ching‐Kang; Brill, Elliott; Krasnoperova, Nataliia V.; Eversole-Cire, Pamela; Kleyner, Yelena; Taylor, Allen; Simon, Melvin I.; Grimm, Christian; Remé, Charlotte E.; Lem, Janis

doi:10.1038/ng984

Cited by 236 publications

(196 citation statements)

References 34 publications

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“…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. These findings are consistent with reports in the literature indicating that light damage can occur independent of phototransduction (34) and that photooxidative mechanisms are involved (35,36). Depending on the conditions, light damage can also originate within photoreceptor cells or RPE, although the greatest damage is reported for RPE (36).…”

Section: Discussionsupporting

confidence: 82%

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.

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: Discussionsupporting

confidence: 82%

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.

111

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“…Since the only effect of the mutation in both cases was to prolong the light responses of the rods, it seemed possible that light was triggering apoptosis by activating transduction either for too long or too strongly. This notion was elegantly proved by Hao and collaborators (28) in the following way. The mutant animals lacking either rhodopsin kinase or arrestin were mated with another strain of mutant mice that lacked the gene for the rod transducin a subunit.…”

Section: Continuous Light Kills By Activating Transductionmentioning

confidence: 83%

Why photoreceptors die (and why they don't)

Fain

2006

BioEssays

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Light can kill the photoreceptors of the eye, not only very bright direct sunlight, but more moderate illumination if the light is present continuously. Recent experiments show that rod apoptosis can be triggered by strong and constant activation of transduction, and that death can be prevented if transduction is inhibited even though the eye is illuminated. Vitamin A deficiency and genetically inherited diseases, such as some forms of retinitis pigmentosa and Leber congenital amaurosis, appear to kill like this: transduction is activated at a high rate and continuously, and this causes the rods to die. Why does transduction kill? Our best guess is that continuous activation produces a prolonged lowering of the Ca2+ concentration, which is also thought to kill neurons in tissue culture and during the development of the nervous system. To prevent death in constant light, rods have evolved protective mechanisms including modulation of channels and ion transport to keep the Ca2+ from going too low. Prolonged light exposure also causes migration of transduction proteins from one part of the cell to another and a reversible shortening of the rod outer segments, the part of the cell that contains the pigment rhodopsin. All of these mechanisms are at work in the normal eye to reduce transduction and prevent the Ca2+ concentration from dropping too low for too long a time. That most of us retain our vision our entire lives is a testament to their effectiveness. BioEssays 28: 344–354, 2006. © 2006 Wiley Periodicals, Inc.

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“…Light as pathogenic stimulus uses at least two different pathways to induce the apoptotic program. Activation and choice of a particular pathway seem to depend on the intensity and duration of light exposure (Hao et al, 2002). Thus, a compound effective in the protection against acute bright light, such as Epo, may not necessarily be protective against long-lasting low-level light exposure.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

Grimm¹,

Wenzel²,

Stanescu³

et al. 2004

J. Neurosci.

112

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Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinant human Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa (RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments.

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Evidence for two apoptotic pathways in light-induced retinal degeneration

Cited by 236 publications

References 34 publications

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

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

Why photoreceptors die (and why they don't)

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

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