Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration

Lenis, Tamara L.; Hu, Jane; Ng, Sze Yin; Jiang, Zhong‐Xing; Sarfare, Shanta; Lloyd, Monte; Esposito, Nicholas J.; Samuel, William; Jaworski, Cynthia; Bok, Dean; Finnemann, Silvia C.; Radeke, Monte J.; Redmond, T. Michael; Travis, Gabriel H.; Radu, Roxana A.

doi:10.1073/pnas.1802519115

Cited by 123 publications

(145 citation statements)

References 35 publications

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“…Recently, it was shown that bisretinoids formation can be initiated endogenously in the RPE, independently of the photoreceptor pathway, from the free retinaldehydes released after rhodopsin proteolysis. Lenis et al showed that the absence of ABCA4 in the RPE internal membranes led to the enhanced deposition of bisretinoids . In rodents, RPE cells in the central retina contain a higher level of lipofuscin and a lower level of melanin than in the peripheral retina .…”

Section: Discussionmentioning

confidence: 99%

“…Lenis et al showed that the absence of ABCA4 in the RPE internal membranes led to the enhanced deposition of bisretinoids. 8 In rodents, RPE cells in the central retina contain a higher level of lipofuscin and a lower level of melanin than in the peripheral retina. 40,41 The RPE degeneration induced by blue light was mainly located in the central area of eyes in pigmented Abca4 −/− mice, consistent with the spatial distribution of phototoxic RPE lipofuscin and RPE melanin that is known to have antioxidative properties.…”

Section: Discussionmentioning

confidence: 99%

“…8 Biochemical evidence has illustrated that ABCA4 protein translocates N-ret-PE (conjugate of all-trans-retinal and phosphatidylethanolamine [PE]) and 11c-N-ret-PE (conjugate of 11-cis-retinal and PE) to the cytoplasmic side of the disk membrane and RPE endolysosomes, thereby acting in the clearance of all-trans-retinal and 11-cis-retinal. [8][9][10] Lack of functional ABCA4 protein induces the accumulation of N-ret-PE, further resulting in the formation of diretinoid-pyridinium-phosphatidylethanolamine (A2PE) in the disk, N-retinylidene-N-retinylethanolamine (A2E) and other bisretinoids, the main constituents of lipofuscin in RPE cells. 11,12 A2E was proven to be an initiator in the process of blue light-induced apoptosis and necroptosis of RPE cells.…”

Section: Introductionmentioning

confidence: 99%

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Fundus autofluorescence, spectral‐domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model

et al. 2020

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Stargardt disease (STGD1), known as inherited retinal dystrophy, is caused by ABCA4 mutations. The pigmented Abca4−/− mouse strain only reflects the early stage of STGD1 since it is devoid of retinal degeneration. This blue light‐illuminated pigmented Abca4−/− mouse model presented retinal pigment epithelium (RPE) and photoreceptor degeneration which was similar to the advanced STGD1 phenotype. In contrast, wild‐type mice showed no RPE degeneration after blue light illumination. In Abca4−/− mice, the acute blue light diminished the mean autofluorescence (AF) intensity in both fundus short‐wavelength autofluorescence (SW‐AF) and near‐infrared autofluorescence (NIR‐AF) modalities correlating with reduced levels of bisretinoid‐fluorophores. Blue light‐induced RPE cellular damage preceded the photoreceptors loss. In late‐stage STGD1‐like patient and blue light‐illuminated Abca4−/− mice, lipofuscin and melanolipofuscin granules were found to contribute to NIR‐AF, indicated by the colocalization of lipofuscin‐AF and NIR‐AF under the fluorescence microscope. In this mouse model, the correlation between in vivo and ex vivo assessments revealed histological characteristics of fundus AF abnormalities. The flecks which are hyper AF in both SW‐AF and NIR‐AF corresponded to the subretinal macrophages fully packed with pigment granules (lipofuscin, melanin, and melanolipofuscin). This mouse model, which has the phenotype of advanced STGD1, is important to understand the histopathology of Stargardt disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fundus autofluorescence, spectral‐domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model

et al. 2020

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“…Highly significant and large (58%) foveal upregulation was only observed in pigment epithelial cells but not in rods and cones, in which ABCA4 is also expressed. Stargardt disease, caused by mutations in the ABCA4 gene, may thus originate in fovea-specific dysfunction of pigment epithelial cells (Lenis et al, 2018). Therapy for Stargardt disease should therefore focus on gene replacement or editing not only of photoreceptors but also of pigment epithelial cells.…”

Section: Functionally Intact Human Retinamentioning

confidence: 99%

Cell types of the human retina and its organoids at single-cell resolution: developmental convergence, transcriptomic identity, and disease map

Cowan

Renner

Gennaro

et al. 2019

Preprint

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How closely human organoids recapitulate cell-type diversity and cell-type maturation of their target organs is not well understood. We developed human retinal organoids with multiple nuclear and synaptic layers. We sequenced the RNA of 158,844 single cells from these organoids at six developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable 'developed' state at a rate similar to human retina development in vivo and the transcriptomes of organoid cell types converged towards the transcriptomes of adult peripheral retinal cell types. The expression of disease-associated genes was significantly cell-type specific in adult retina and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in adult human retinas.

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“…In contrast to the current study, Mookherjee et al (2015) employed the photoreceptor-specific rhodopsin kinase promoter to drive expression of the RP2 gene, and using this specific promoter achieved a partial rescue of the cone phenotype in one of the null RP2 mouse models, but had no beneficial effect on the rod phenotype. In the context of the requirement or otherwise for transgene expression in multiple cell types, it is notable that a recent study of ABCA4-linked Stargardt disease demonstrated that, while ABCA4 is expressed in the RPE at only about 1% the level of that in photoreceptors, restricted expression of ABCA4 solely in RPE cells provided partial rescue of the photoreceptor degeneration in ABCA4 -/mice (Lenis et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Modelling and rescue of RP2 Retinitis Pigmentosa using iPSC Derived Retinal Organoids

Lane¹,

Jovanović²,

Shortall

et al. 2020

Preprint

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Mutations in RP2 lead to a severe form of X-linked retinitis pigmentosa (XLRP). RP2 functions as a GTPase activating protein (GAP) for the small GTPase ARL3, which is essential for cilia function and for photoreceptor development and maintenance. The mechanisms of RP2 associated retinal degeneration in humans are poorly understood, and genetically engineered animal models of RP2 XLRP present with differing retinal phenotypes and slow degeneration suggesting potential species differences. Here, we developed CRISPR gene edited isogenic RP2 knock-out (RP2 KO) induced pluripotent stem cells (iPSC) and RP2 patient derived iPSC to produce 3D retinal organoids as a human retinal disease model. The isogenic RP2 KO retinal organoids and two unrelated RP2 patient iPSC lines produced retinal organoids with a defined photoreceptor cell layer (ONL) containing rod and cone photoreceptors. Strikingly the RP2 KO and RP2 patient derived organoids showed a thinning of the ONL by 180 days (D180) of culture, which was associated with a spike in cell death in the ONL at D150 of differentiation.RNA sequencing confirmed induction of cell death pathways in the RP2 null organoids at this stage. Photoreceptor cell death and ONL thinning was attributed to cells undergoing terminal rod cell differentiation characterized by reduced RHO expression and fewer rhodopsin immunoreactive photoreceptors. Gene augmentation with a human RP2 transgene in an AAV2/5 vector efficiently transduced RP2 KO organoids and led to high levels of RP2 expression in both rods and cones. Importantly, the viral transduction significantly increased ONL thickness and restored rhodopsin expression, suggesting rescue of the RP2 degeneration phenotype. These data show that 3D retinal organoids can be used to model molecular defects associated with inherited retinal disease, photoreceptor cell death and also to test potential therapies targeted to prevent photoreceptor degeneration.

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Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration

Cited by 123 publications

References 35 publications

Fundus autofluorescence, spectral‐domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model

Fundus autofluorescence, spectral‐domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model

Cell types of the human retina and its organoids at single-cell resolution: developmental convergence, transcriptomic identity, and disease map

Modelling and rescue of RP2 Retinitis Pigmentosa using iPSC Derived Retinal Organoids

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