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

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’.

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Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration

Ophthalmology ◽

10.1016/s0161-6420(00)00419-x ◽

2000 ◽

Vol 107 (12) ◽

pp. 2256-2266 ◽

Cited By ~ 53

Author(s):

Ann H Milam ◽

Christine A Curcio ◽

Artur V Cideciyan ◽

Samir Saxena ◽

Sinoj K John ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Retinal Degeneration ◽

Regional Variation ◽

Late Onset ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Function ◽

Photoreceptor Degeneration

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Faculty Opinions recommendation of Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1127856.584947 ◽

2008 ◽

Author(s):

Steven A Rosenzweig

Keyword(s):

Retinal Pigment Epithelium ◽

Retinal Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment

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

Molecular and Cellular Biology ◽

10.1128/mcb.00295-17 ◽

2017 ◽

Vol 37 (24) ◽

Cited By ~ 4

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.

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

Cells ◽

10.3390/cells9030771 ◽

2020 ◽

Vol 9 (3) ◽

pp. 771 ◽

Cited By ~ 1

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.

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Recessive Familial Spastic Paraplegia with Retinal Degeneration

Acta geneticae medicae et gemellologiae ◽

10.1017/s1120962300023878 ◽

1974 ◽

Vol 23 (S1) ◽

pp. 249-252 ◽

Cited By ~ 3

Author(s):

W. Macrae ◽

J. Stieffel ◽

A.B. Todorov

Keyword(s):

Retinal Pigment Epithelium ◽

Retinal Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Spastic Paraplegia ◽

Reticular Pattern ◽

Ocular Symptoms ◽

Window Effect ◽

Familial Spastic Paraplegia ◽

The Right

A family is described in which spastic paraplegia and retinal degeneration were observed in 5 out of 11 sibs in one generation. All affected members of this family had the onset of bilateral ocular symptoms during the fourth to fifth decade. Visual impairment was slowly progressive and ranged from 20/25 to 20/100.There was a macular and perimacular speckling with small, irregular, discrete spots and central pigment proliferation, at the level of the pigment epithelium. Fluorescein angiography revealed patches of proliferating retinal pigment epithelium blocking transmission of fluorescein, surrounded by a larger area of disruption of the retinal pigment epithelium giving a “window-effect” choroidal pattern. The right macula showed a nonspecific, nonfluorescent, reticular pattern.The most likely explanation of the ocular findings was a retinal degeneration involving the retinal pigment epithelium and/or the chorio-capillaries. Extensive laboratory work was negative.

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