The Proteomics of Drusen

Crabb, John W.

doi:10.1101/cshperspect.a017194

Cited by 80 publications

(59 citation statements)

References 125 publications

(159 reference statements)

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“…Using immunofluorescence, we observed the accumulation of several proteins described previously as characteristic for drusen in human AMD samples. Although our analysis did not exhaust the documented components of drusen in human disease (Crabb, ), nevertheless, our data show the appearance of these sub‐RPE deposits, even in the absence of known confounding mutations or variants correlating with the risk of the disease.…”

Section: Discussionmentioning

confidence: 71%

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

et al. 2020

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Methylation of the regulatory region of the elongation of very‐long‐chain fatty acids‐like 2 (ELOVL2) gene, an enzyme involved in elongation of long‐chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age‐associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age‐related eye diseases. We show that an age‐related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5‐Aza‐2’‐deoxycytidine (5‐Aza‐dc) leads to increased Elovl2 expression and rescue of age‐related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2‐specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well‐established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age‐related eye diseases.

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Section: Discussionmentioning

confidence: 71%

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

et al. 2020

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“…Drusen are extracellular debris deposits, containing a variety of RPE waste products, lipids, polysaccharides, glycosaminoglycans, and proteins, which accumulate below the RPE during aging. 28 Drusen create a barrier to diffusion of metabolites in Bruch's membrane, hampering RPE nutrition from the choroid, and localized hypoxia overlying regions of drusen deposition may increase the risk of VEGF upregulation because hypoxia is a major inducer of VEGF gene transcription. 29 Furthermore, drusen proteins are involved in inflammation, which may activate microglia to stimulate RPE cells to express VEGF via releasing cytokines.…”

Section: Discussionmentioning

confidence: 99%

Intraocular Vascular Endothelial Growth Factor Levels in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration

Hata

Yamashiro

Ooto

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Hata M, Yamashiro K, Ooto S, et al. Intraocular vascular endothelial growth factor levels in pachychoroid neovasculopathy and neovascular agerelated macular degeneration. Invest Ophthalmol Vis Sci. 2017;58:292-298. DOI:10.1167/iovs.16-20967 PURPOSE. To investigate the difference in intraocular vascular endothelial growth factor (VEGF) concentration between pachychoroid neovasculopathy and neovascular age-related macular degeneration (nAMD) and its associations with responses to three monthly anti-VEGF injections as an initial treatment for the two conditions.METHODS. This study included nine eyes with treatment-naïve pachychoroid neovasculopathy and 21 eyes with treatment-naïve nAMD. Before the initial intravitreal anti-VEGF injection, aqueous humor samples were collected and the concentration of VEGF was measured using enzyme-linked immunosorbent assay. The concentration was compared between the two conditions, and its associations with responses to anti-VEGF therapy were investigated. RESULTS.The mean VEGF concentration in pachychoroid neovasculopathy was significantly lower than that in nAMD (63.4 6 17.8 pg/ml and 89.8 6 45.0 pg/ml, respectively; P ¼ 0.035). The VEGF concentration was associated with the presence or absence of drusen (b ¼ 0.503, P ¼ 0.004). After anti-VEGF therapy, 6 (66.7%) of 9 eyes with pachychoroid neovasculopathy and 17 (81.0%) of 21 eyes with nAMD achieved dry macula (P ¼ 0.640). Dry macula at 3 months and 12 months was significantly associated with a low VEGF concentration in pachychoroid neovasculopathy (P ¼ 0.013 and P ¼ 0.042, respectively), but not in nAMD (P ¼ 0.108 and P ¼ 0.219). CONCLUSIONS.The mean VEGF concentration in pachychoroid neovasculopathy was lower than that in nAMD, suggesting that the way in which VEGF is involved in angiogenesis may differ between pachychoroid neovasculopathy and nAMD.

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“…While a complete understanding of the disease process remains elusive, considerable progress has been made in elucidating the molecular composition of drusen, which consist of approximately half protein and half lipid (Crabb, 2014; Wang et al, 2010). Numerous proteins, including all the major proteins of the complement pathway, TIMP3, APOJ, Annexin, Crystallins, APOE, Vitronectin and Amyloid β (Aβ), have been identified in drusen deposits, which share several similarities to aggregates formed in Alzheimer’s disease (AD) (Ohno-Matsui, 2011).…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

et al. 2017

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Summary Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human induced pluripotent stem cells (hiPSCs) from patients diagnosed with AMD, including two with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from AMD donors showed significantly increased complement and inflammatory factors, most exaggerated in ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discovered that Nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins, inflammatory and complement factors, while upregulating nucleosome, ribosome and chromatin-modifying genes. Thus, targeting NAM-regulated pathways is a promising avenue for developing therapeutics to combat AMD.

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The Proteomics of Drusen

Cited by 80 publications

References 125 publications

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

Intraocular Vascular Endothelial Growth Factor Levels in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration

Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

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