Faculty Opinions recommendation of mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice.

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4−/− (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4−/− mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY–treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY–treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.

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

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2015.0376 ◽

2016 ◽

Vol 374 (2079) ◽

pp. 20150376 ◽

Cited By ~ 7

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’.

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Light-Evoked Responses of the Retinal Pigment Epithelium: Changes Accompanying Photoreceptor Loss in the Mouse

Journal of Neurophysiology ◽

10.1152/jn.00088.2010 ◽

2010 ◽

Vol 104 (1) ◽

pp. 391-402 ◽

Cited By ~ 24

Author(s):

Ivy S. Samuels ◽

Gwen M. Sturgill ◽

Gregory H. Grossman ◽

Mary E. Rayborn ◽

Joe G. Hollyfield ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Structural Changes ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Disease ◽

Rod Photoreceptor ◽

Evoked Responses ◽

Photoreceptor Degeneration ◽

Rod Photoreceptors ◽

Slow Piii

Mutations in genes expressed in the retinal pigment epithelium (RPE) underlie a number of human inherited retinal disorders that manifest with photoreceptor degeneration. Because light-evoked responses of the RPE are generated secondary to rod photoreceptor activity, RPE response reductions observed in human patients or animal models may simply reflect decreased photoreceptor input. The purpose of this study was to define how the electrophysiological characteristics of the RPE change when the complement of rod photoreceptors is decreased. To measure RPE function, we used an electroretinogram (dc-ERG)-based technique. We studied a slowly progressive mouse model of photoreceptor degeneration ( Prph Rd2/+), which was crossed onto a Nyxnob background to eliminate the b-wave and most other postreceptoral ERG components. On this background, Prph Rd2/+ mice display characteristic reductions in a-wave amplitude, which parallel those in slow PIII amplitude and the loss of rod photoreceptors. At 2 and 4 mo of age, the amplitude of each dc-ERG component (c-wave, fast oscillation, light peak, and off response) was larger in Prph Rd2/+ mice than predicted by rod photoreceptor activity (RmP3) or anatomical analysis. At 4 mo of age, the RPE in Prph Rd2/+ mice showed several structural abnormalities including vacuoles and swollen, hypertrophic cells. These data demonstrate that insights into RPE function can be gained despite a loss of photoreceptors and structural changes in RPE cells and, moreover, that RPE function can be evaluated in a broader range of mouse models of human retinal disease.

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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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Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium

Experimental Eye Research ◽

10.1016/s0014-4835(86)80023-9 ◽

1986 ◽

Vol 43 (4) ◽

pp. 561-573 ◽

Cited By ~ 94

Author(s):

Martin L. Katz ◽

Christine M. Drea ◽

Graig E. Eldred ◽

Helen H. Hess ◽

W. Gerald Robison

Keyword(s):

Retinal Pigment Epithelium ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Photoreceptor Degeneration

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Retinal Pigment Epithelium Defects Accelerate Photoreceptor Degeneration in Cell Type–Specific Knockout Mouse Models of Choroideremia

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.09-4892 ◽

2010 ◽

Vol 51 (10) ◽

pp. 4913 ◽

Cited By ~ 43

Author(s):

Tanya Tolmachova ◽

Silene T. Wavre-Shapton ◽

Alun R. Barnard ◽

Robert E. MacLaren ◽

Clare E. Futter ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Mouse Models ◽

Knockout Mouse ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Photoreceptor Degeneration ◽

Cell Type ◽

Cell Type Specific

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mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Journal of Clinical Investigation ◽

10.1172/jci44303 ◽

2011 ◽

Vol 121 (1) ◽

pp. 369-383 ◽

Cited By ~ 137

Author(s):

Chen Zhao ◽

Douglas Yasumura ◽

Xiyan Li ◽

Michael Matthes ◽

Marcia Lloyd ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Photoreceptor Degeneration

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The Retinal Pigment Epithelium in Visual Function

Physiological Reviews ◽

10.1152/physrev.00021.2004 ◽

2005 ◽

Vol 85 (3) ◽

pp. 845-881 ◽

Cited By ~ 1353

Author(s):

Olaf Strauss

Keyword(s):

Retinal Pigment Epithelium ◽

Visual Function ◽

Functional Unit ◽

Current Knowledge ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Other ◽

Photoreceptor Degeneration ◽

Multiple Functions ◽

Outer Segments

Located between vessels of the choriocapillaris and light-sensitive outer segments of the photoreceptors, the retinal pigment epithelium (RPE) closely interacts with photoreceptors in the maintenance of visual function. Increasing knowledge of the multiple functions performed by the RPE improved the understanding of many diseases leading to blindness. This review summarizes the current knowledge of RPE functions and describes how failure of these functions causes loss of visual function. Mutations in genes that are expressed in the RPE can lead to photoreceptor degeneration. On the other hand, mutations in genes expressed in photoreceptors can lead to degenerations of the RPE. Thus both tissues can be regarded as a functional unit where both interacting partners depend on each other.

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