Accelerated Accumulation of Lipofuscin Pigments in the RPE of a Mouse Model for<i>ABCA4</i>-Mediated Retinal Dystrophies following Vitamin A Supplementation

Radu, Roxana A.; Yuan, Quan; Hu, Jane; Peng, Jennifer H.; Lloyd, Monte; Nusinowitz, Steven; Bok, Dean; Travis, Gabriel H.

doi:10.1167/iovs.07-1470

Cited by 152 publications

(134 citation statements)

References 48 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…A2E exhibits several mechanisms of cytotoxicity and is implicated in the pathogenesis of STGD1 (26 -32). Interestingly, Abca4 Ϫ/Ϫ mice exhibit dysregulation of the complement system and signs of complement-mediated inflammation in the RPE before the onset of photoreceptor degeneration (25,33). These observations establish a connection between bisretinoid accumulation and complement activation in vivo.…”

mentioning

confidence: 72%

See 1 more Smart Citation

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Radu

Jiang

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: AMD and STGD1 are blinding diseases with similar clinical presentations but unrelated genetic causes. Results: Bisretinoid-dependent complement reactivity on RPE cells involves the alternative pathway and depends on the CFH haplotype. Conclusion: Inefficient CFH synthesis because of either Y402H and I62V substitutions or bisretinoid accumulation predisposes RPE cells to disease. Significance: These results suggest a common inflammatory etiology for AMD and STGD1.

show abstract

mentioning

confidence: 72%

“…Similar to STGD1 patients, mice with a knockout mutation in the Abca4 gene accumulate fluorescent lipofuscin granules and bisretinoids, such as A2E, in the RPE (24,25). A2E exhibits several mechanisms of cytotoxicity and is implicated in the pathogenesis of STGD1 (26 -32).…”

mentioning

confidence: 99%

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Radu

Jiang

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Marked bisretinoid accumulation is replicated not only in Abca4 null mutant mice (9,10) but also in mice deficient in retinol dehydrogenase-8 and dehydrogenase-12 (Rdh8; Rdh12) (11)(12)(13). In addition, the relationship between RPE lipofuscin accumulation and retinal disease is evidenced in the Abca4 mouse model by complement dysregulation, carbonyl-deposition, thickening of Bruch's membrane, and a progressive loss of photoreceptor cells (11,(14)(15)(16)(17).…”

mentioning

confidence: 97%

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

View full text Add to dashboard Cite

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

show abstract

“…As indicated by the authors, the efficiency with which native vitamin A is replaced by C20-D 3 -vitamin A remains to be determined (55). An increase in total vitamin A intake might also potentiate the drive toward bisretinoid formation (56).…”

Section: Therapeutic Approaches That Target Bisretinoid: Clinical Andmentioning

confidence: 98%

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Sparrow

2016

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

View full text Add to dashboard Cite

Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.age-related macular degeneration | vitamin A-aldehyde adducts | bisretinoids | retinal pigment epithelium | photoreceptor cells Age-related macular degeneration (AMD) is a complex disorder that is predicted to have a growing impact on elderly populations. Although the cause of central vision loss in AMD is the progressive impairment of photoreceptor cells, the disease is generally thought to begin with dysfunctioning of retinal pigment epithelium (RPE) and adverse changes in subjacent Bruch's membrane (1, 2). The early stage of the disease is typically marked by extracellular accumulations (drusen) between RPE and Bruch's membrane. Progression to advanced disease is defined by delineated areas devoid of RPE and photoreceptor cell loss (atrophic AMD) and/or abnormal growth of blood vessels underneath RPE or within the subretinal space (neovascular AMD). AMD Risk FactorsAMD susceptibility is influenced by multiple factors of both genetic and environmental origin. Predisposing genetic factors account for 71% of the variation in disease risk among individuals (3). Currently, 52 independently associated genetic variants at 34 loci are known to account for ∼50% of AMD heritability (4). The genes implicated by these variants belong to multiple systems some of which are associated with the complement pathway, lipid metabolism, and maintenance of extracellular matrix (5, 6). Nevertheless, many individuals carrying risk variants do not develop AMD.Two loci, CFH (complement factor H; 1q31) and ARMS2/HTRA1 (age-related maculopathy susceptibility 2/high-temperature requirement factor A1; 10q26), make the greatest contribution to AMD risk. Variants at the ARMS2/HTRA1 and CFH loci significantly increase risk for progression to both the atrophic and neovascular forms of AMD, although the magnitude of the association of the ARMS2/HTRA1 risk allele is somewhat greater for the neovascular phenotype of late AMD, whereas CFH risk variants favor progression toward geogr...

show abstract

Accelerated Accumulation of Lipofuscin Pigments in the RPE of a Mouse Model forABCA4-Mediated Retinal Dystrophies following Vitamin A Supplementation

Abstract: Vitamin A supplementation should be avoided in patients with ABCA4 mutations or other retinal or macular dystrophies associated with lipofuscin accumulation in the retinal pigment epithelium.

Cited by 152 publications

References 48 publications

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

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

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Contact Info

Product

Resources

About