scholarly journals Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 771 ◽  
Author(s):  
Marci L. DeRamus ◽  
Stephanie J. Davis ◽  
Sriganesh Ramachandra Rao ◽  
Cyril Nyankerh ◽  
Delores Stacks ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Types ◽  
Protein Glycosylation ◽  
Photoreceptor Layer ◽  
Selective Ablation ◽  
Rpe Atrophy ◽  
Structural Loss

Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhddsflx/flx). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation.

scholarly journals Early Detection of Incipient Retinal Pigment Epithelium Atrophy Overlying Drusen with Fundus Autofluorescence vs. Spectral Domain Optical Coherence Tomography

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Anabel Rodríguez ◽  
Marc Biarnés ◽  
Rosa M. Coco-Martin ◽  
Anna Sala-Puigdollers ◽  
Jordi Monés
Keyword(s):  
Optical Coherence Tomography ◽  
Retinal Pigment Epithelium ◽  
Median Time ◽  
Pigment Epithelium ◽  
Fundus Autofluorescence ◽  
Retinal Pigment ◽  
Geographic Atrophy ◽  
Optical Coherence ◽  
Rpe Atrophy ◽  
Sd Oct

Purpose. This study aims to find out which tool, fundus autofluorescence (FAF) or spectral domain optical coherence tomography (SD-OCT), is more sensitive in detecting retinal pigment epithelium (RPE) demise overlying drusen and can, therefore, help predict geographic atrophy (GA) appearance in Age-Related Macular Degeneration (AMD). Methods. A single-site, retrospective, observational, longitudinal study was conducted. Patients with intermediate AMD (iAMD) (large (>125 μm) or intermediate (63–125 μm) drusen with hyper/hypopigmentation) with a minimum follow-up of 18 months were included. Drusen with overlying incipient RPE atrophy were identified on SD-OCT defined as choroidal hypertransmission or nascent geographic atrophy (nGA). These selected drusen were, then, traced backwards in time to determine if incipient RPE atrophy overlying drusen was observed on FAF (well-demarcated region of absence of autofluorescence) before, simultaneously, or after having detected the first signs of incipient RPE atrophy on SD-OCT. The number of drusen in which signs of incipient RPE atrophy was detected earlier using FAF or SD-OCT was compared. The time elapsed from the identification with the more sensitive method to the other was recorded and analyzed. Results. One hundred and thirty-three drusen in 22 eyes of 22 patients were included. Of these, 112 (84.2%) drusen showed choroidal hypertransmission and 21(15.8%) nGA. Early signs of atrophy overlying drusen were found simultaneously on SD-OCT and FAF in 52 cases (39.1%, 95% CI 30.8–47.9%), earliest on FAF in 51 (38.3%, 95% CI 30.0–47.2%) and first on SD-OCT in 30 (22.6%, 95% CI 15.8–30.6%; p<0.05). Statistically significant differences were found between both techniques (p=0.005), with FAF detecting it earlier than SD-OCT. When RPE atrophy was found first on FAF, the median time to diagnosis with SD-OCT was 6.6 months (95% CI 5.5 to 8.6), while if detection occurred earlier on SD-OCT, the median time until identification with FAF was 12.6 months (95% CI 6.0 to 23.4; p=0.0003). Conclusions. In iAMD cases in which early atrophy overlying drusen is not detected simultaneously in FAF and SD-OCT, FAF was significantly more sensitive. Nevertheless, a multimodal approach is recommended and required to evaluate these patients.

scholarly journals Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation

2016 ◽  
Vol 374 (2079) ◽  
pp. 20150376 ◽  
Author(s):  
Junhua Wang ◽  
Peter D. Westenskow ◽  
Mingliang Fang ◽  
Martin Friedlander ◽  
Gary Siuzdak
Keyword(s):  
Stem Cell ◽  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Photoreceptor Degeneration ◽  
Quantitative Metabolomics ◽  
Fatty Acid Amides ◽  
Age Related

Photoreceptor degeneration is characteristic of vision-threatening diseases including age-related macular degeneration. Photoreceptors are metabolically demanding cells in the retina, but specific details about their metabolic behaviours are unresolved. The quantitative metabolomics of retinal degeneration could provide valuable insights and inform future therapies. Here, we determined the metabolomic ‘fingerprint’ of healthy and dystrophic retinas in rat models using optimized metabolite extraction techniques. A number of classes of metabolites were consistently dysregulated during degeneration: vitamin A analogues, fatty acid amides, long-chain polyunsaturated fatty acids, acyl carnitines and several phospholipid species. For the first time, a distinct temporal trend of several important metabolites including DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), all- trans -retinal and its toxic end-product N -retinyl- N -retinylidene-ethanolamine were observed between healthy and dystrophic retinas. In this study, metabolomics was further used to determine the temporal effects of the therapeutic intervention of grafting stem cell-derived retinal pigment epithelium (RPE) in dystrophic retinas, which significantly prevented photoreceptor atrophy in our previous studies. The result revealed that lipid levels such as phosphatidylethanolamine in eyes were restored in those animals receiving the RPE grafts. In conclusion, this study provides insight into the metabolomics of retinal degeneration, and further understanding of the efficacy of RPE transplantation. This article is part of the themed issue ‘Quantitative mass spectrometry’.

scholarly journals Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

2008 ◽  
Vol 22 (22) ◽  
pp. 3147-3157 ◽  
Author(s):  
J. W. Kim ◽  
K. H. Kang ◽  
P. Burrola ◽  
T. W. Mak ◽  
G. Lemke
Keyword(s):  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment

scholarly journals Multiocular organoids from human induced pluripotent stem cells displayed retinal, corneal, and retinal pigment epithelium lineages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Helena Isla-Magrané ◽  
Anna Veiga ◽  
José García-Arumí ◽  
Anna Duarri
Keyword(s):  
Stem Cells ◽  
Retinal Pigment Epithelium ◽  
Epithelial Cells ◽  
Pluripotent Stem Cells ◽  
Eye Development ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Types ◽  
Induced Pluripotent ◽  
Different Cell Types

Abstract Background Recently, great efforts have been made to design protocols for obtaining ocular cells from human stem cells to model diseases or for regenerative purposes. Current protocols generally focus on isolating retinal cells, retinal pigment epithelium (RPE), or corneal cells and fail to recapitulate the complexity of the tissue during eye development. Here, the generation of more advanced in vitro multiocular organoids from human induced pluripotent stem cells (hiPSCs) is demonstrated. Methods A 2-step method was established to first obtain self-organized multizone ocular progenitor cells (mzOPCs) from 2D hiPSC cultures within three weeks. Then, after the cells were manually isolated and grown in suspension, 3D multiocular organoids were generated to model important cellular features of developing eyes. Results In the 2D culture, self-formed mzOPCs spanned the neuroectoderm, surface ectoderm, neural crest, and RPE, mimicking early stages of eye development. After lifting, mzOPCs developed into different 3D multiocular organoids composed of multiple cell lineages including RPE, retina, and cornea, and interactions between the different cell types and regions of the eye system were observed. Within these organoids, the retinal regions exhibited correct layering and contained all major retinal cell subtypes as well as retinal morphological cues, whereas the corneal regions closely resembled the transparent ocular-surface epithelium and contained of corneal, limbal, and conjunctival epithelial cells. The arrangement of RPE cells also formed organoids composed of polarized pigmented epithelial cells at the surface that were completely filled with collagen matrix. Conclusions This approach clearly demonstrated the advantages of the combined 2D-3D construction tissue model as it provided a more ocular native-like cellular environment than that of previous models. In this complex preparations, multiocular organoids may be used to model the crosstalk between different cell types in eye development and disease. Graphical abstract

scholarly journals Selective Ablation of Megalin in the Retinal Pigment Epithelium Results in Megaophthalmos, Macromelanosome Formation and Severe Retina Degeneration

2019 ◽  
Vol 60 (1) ◽  
pp. 322 ◽  
Author(s):  
Tina Storm ◽  
Thomas Burgoyne ◽  
Joshua L. Dunaief ◽  
Erik I. Christensen ◽  
Clare Futter ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Selective Ablation

scholarly journals Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration

2017 ◽  
Vol 37 (24) ◽  
Author(s):  
Aswin Pyakurel ◽  
Delphine Balmer ◽  
Marc K. Saba-El-Leil ◽  
Caroline Kizilyaprak ◽  
Jean Daraspe ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Side Effects ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Ocular Side ◽  
Extracellular Signal

ABSTRACT Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects.

scholarly journals Multimodal imaging of Hypotrichosis with juvenile macular dystrophy: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Giovanna Carnovale Scalzo ◽  
Adriano Carnevali ◽  
Gabriele Piccoli ◽  
Domenico Ceravolo ◽  
Donatella Bruzzichessi ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Multimodal Imaging ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Unknown Origin ◽  
Clinical Findings ◽  
Macular Dystrophy ◽  
Photoreceptor Layer ◽  
Inherited Retinal Dystrophies ◽  
Italian Case

Abstract Background To report the first Italian case of hypotrichosis with juvenile macular dystrophy complicated by macular neovascularization diagnosed through multimodal imaging. Case presentation An 11-year-old boy was referred to our Institution for bilateral maculopathy of unknown origin. Multimodal imaging helps the diagnosis of Juvenile Macular Dystrophy with Hypotrichosis (HJMD). Fundus examination showed several alterations of the retinal pigment epithelium and circular pigmented area of chorioretinal atrophy. Structural spectral domain optical coherence tomography (OCT) showed some backscattering phenomenon with several alterations of retinal pigment epithelium and photoreceptor layer in both eyes. Moreover, OCT showed hyperreflective lesion beneath the neuroepithelium in left eye. OCT angiography (OCT-A) revealed a pathologic neovascular network in choriocapillaris plexus, probably the result of a fibrovascular membrane. Multifocal electroretinograms (MfERGs) showed functional alterations in 12.22° of the central retina. In order to confirm the suspicion of HJMD, the child and both parents underwent genetic testing. Both parents resulted to be heterozygous healthy carriers of a single variation. Conclusion Multimodal imaging, in particular OCT-A, is a useful aid, along to clinical findings and genetics, for the diagnosis of inherited retinal dystrophies.

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