Retina Metabolism and Metabolism in the Pigmented Epithelium: A Busy Intersection

Hurley, James B.

doi:10.1146/annurev-vision-100419-115156

Cited by 105 publications

(93 citation statements)

References 168 publications

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“…With ex vivo analysis we localized F263 in GCL and INL while it was not detected in ONL. The identification of F263 as a target of PKG and its high phosphorylation in rd1 compared to WT may suggest a change in retinal energy metabolism during degeneration and may also help to understand the mechanism of aerobic glycolysis in the retina, which remains relatively poorly understood to date [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

et al. 2022

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Inherited retinal diseases (IRDs) are a group of neurodegenerative disorders that lead to photoreceptor cell death and eventually blindness. IRDs are characterised by a high genetic heterogeneity, making it imperative to design mutation-independent therapies. Mutations in a number of IRD disease genes have been associated with a rise of cyclic 3’,5’-guanosine monophosphate (cGMP) levels in photoreceptors. Accordingly, the cGMP-dependent protein kinase (PKG) has emerged as a new potential target for the mutation-independent treatment of IRDs. However, the substrates of PKG and the downstream degenerative pathways triggered by its activity have yet to be determined. Here, we performed kinome activity profiling of different murine organotypic retinal explant cultures (diseased rd1 and wild-type controls) using multiplex peptide microarrays to identify proteins whose phosphorylation was significantly altered by PKG activity. In addition, we tested the downstream effect of a known PKG inhibitor CN03 in these organotypic retina cultures. Among the PKG substrates were potassium channels belonging to the Kv1 family (KCNA3, KCNA6), cyclic AMP-responsive element-binding protein 1 (CREB1), DNA topoisomerase 2-α (TOP2A), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (F263), and the glutamate ionotropic receptor kainate 2 (GRIK2). The retinal expression of these PKG targets was further confirmed by immunofluorescence and could be assigned to various neuronal cell types, including photoreceptors, horizontal cells, and ganglion cells. Taken together, this study confirmed the key role of PKG in photoreceptor cell death and identified new downstream targets of cGMP/PKG signalling that will improve the understanding of the degenerative mechanisms underlying IRDs.

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Section: Discussionmentioning

confidence: 99%

Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

et al. 2022

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“…Future studies are needed to determine if EV RNAs contents can also be transferred from the RPE to other retinal cells and regulate gene expression in the recipient cells. For example, in many ways RPE and photoreceptor cells function together, with coordinated metabolism and RPE cells phagocytosing shed photoreceptor outer segments (42). Since overall retinal function and health depends on these shared processes, it is attractive to hypothesize that EVs may be used for intercellular signaling between the RPE and photoreceptor cells, however further studies are needed to support this hypothesis (43).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The RNA content of extracellular vesicles fromPRPF31^+/−hiPSC-RPE show potential as biomarkers of retinal degeneration

Getachew

Mehrotra

Fernández-Godino

et al. 2022

Preprint

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Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration (IRD) and causes vision loss via dysfunction and death of the photoreceptor cells and retinal pigment epithelium (RPE) of the retina. Mutations in pre-mRNA processing factor 31 (PRPF31) are associated with autosomal dominant RP, and are thought to cause retinal degeneration by causing cell autonomous defects in RPE function. Genetic therapies such as adeno-associated virus (AAV) mediated gene therapy show great promise for treating IRDs, however in many cases it is challenging to measure clinical efficacy in a timely manner because IRDs progress slowly. A potential solution to this challenge is the use of additional outcome measures, such as biomarkers. Extracellular vesicles (EVs) are lipid enclosed vesicles that are secreted by cells and their RNA contents have been proposed as potential biomarkers in cancer and other diseases. We hypothesize EV RNAs can be used as biomarkers of the health status of the neural retina and RPE. To test this hypothesis for the RPE, we used PRPF31+/+ and PRPF31+/− human induced pluripotent stem cell (hiPSC)-derived RPE to investigate the RNAs contained in RPE-derived EVs, and how they change in disease. We also compared the RNA contents of RPE-EVs with the RNAs contained in the hiPSC-RPE cells themselves. We found that EVs from mutant PRPF31+/− hiPSC-RPE cells contain distinct RNAs compared to EV from the control PRPF31+/+ hiPSC-RPE cells, suggesting EV RNA contents change during disease and can potentially serve as biomarkers of retinal degeneration.

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“…This persistent, potentially constructive remodeling could be driven by the diminished numbers of photoreceptors and shortened outer segments-both of which would lead to reduced photoreceptor light absorption and oxygen consumption and, thus, chronic oxidative stress in the retina. In addition, since RPE metabolism depends on photoreceptors [48,49], decreased numbers of photoreceptors might lead to RPE starvation. It has been shown that overexpression of NRF2, a transcription factor that regulates the response to oxidative stress, protects RPE in RP mice [46].…”

Section: Ongoing Potentially Constructive Rpe and Retinal Blood Vesse...mentioning

confidence: 99%

Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

Kajtna

Tsang

Koch

2022

Cell. Mol. Life Sci.

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Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16 weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24 weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24 weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization.

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Retina Metabolism and Metabolism in the Pigmented Epithelium: A Busy Intersection

Cited by 105 publications

References 168 publications

Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

The RNA content of extracellular vesicles fromPRPF31^+/−hiPSC-RPE show potential as biomarkers of retinal degeneration

Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

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Retina Metabolism and Metabolism in the Pigmented Epithelium: A Busy Intersection

Cited by 105 publications

References 168 publications

Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration

The RNA content of extracellular vesicles fromPRPF31+/−hiPSC-RPE show potential as biomarkers of retinal degeneration

Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

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The RNA content of extracellular vesicles fromPRPF31^+/−hiPSC-RPE show potential as biomarkers of retinal degeneration