Dark-Rearing the rd10 Mouse: Implications for Therapy

Lyubarsky, Arkady; Bennett, Jean

doi:10.1007/978-1-4614-0631-0_18

Cited by 23 publications

(20 citation statements)

References 18 publications

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“…Our experiments show that the degeneration accelerated by illumination is slowed by removing the cGMP-gated channels, implicating a contribution by lightinduced increase of cGMP. Interestingly, dark-rearing rd10 mice have been shown to slow degeneration (27,57,58). Our observation that cGMP did not accumulate in dark-adapted rd10 retinas may explain this rescuing effect.…”

Section: Rd10 Retina As a Model System For Degenerationmentioning

confidence: 61%

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The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx

Wang

Reingruber

Woodruff

et al. 2018

Journal of Biological Chemistry

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The retinal degeneration model rd10 contains a missense mutation of the catalytic PDE6 β subunit, which hydrolyzes cGMP in response to light. This model produces cell death more slowly than others caused by PDE6 loss of function, making it of particular interest for studying potential therapeutics. We used morphology, biochemistry, and single-cell physiology to examine the mechanism of rd10 degeneration. Our results show that the mutation produces no alteration of RNA but does dramatically decrease maximal and basal PDE6 activity, apparently caused by a decrease in protein stability and transport. The enzymatic properties of the remaining mutant PDE6 appear to be nearly normal. We demonstrate that an increase in free cGMP, which would result from decreased PDE6 activity and serve to increase opening of the cGMP-gated channels and calcium influx, is an underlying cause of cell death: degeneration of rd10/ double mutants is slower than the parent rd10 line. Paradoxically, degeneration in rd10/ is also slower than in This rescue is correlated with a lowering of cGMP content in retinas and suggests that it may be caused by mislocalization of active PDE6. Single-cell recordings from rd10 rods show that the rates of rise and decay of the response are significantly slower; simulations indicate that these changes are primarily the result of the decrease in PDE6 concentration and rod collecting area. Together, these results provide insights into the complex mechanisms that underlie rd10-mediated retinal degeneration and a cautionary note for analysis of therapeutic interventions.

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Section: Rd10 Retina As a Model System For Degenerationmentioning

confidence: 61%

“…Because dark-rearing slows retinal degeneration in rd10 (27,57,58), all samples used in PDE activity assays were from 3-week-old dark-reared rd10 mice to maximize PDE6 levels. Other genotypes were reared under normal cyclic light (12 h light/12 h dark).…”

Section: Assays Of Pde6 Activity and Inhibition By Pde6␥mentioning

confidence: 99%

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx

Wang

Reingruber

Woodruff

et al. 2018

Journal of Biological Chemistry

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“…It is well established that photoreceptor survival can be prolonged in models of RP by rearing animals in the dark. 21 – 24 However, the conditions underlying the eventual degeneration of photoreceptors with dark rearing are not well understood. 22 In this study, we examined the novel hypothesis that outer retinal oxidative stress occurs in Pde6b rd10 mice independent of light exposure.…”

mentioning

confidence: 99%

Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6b^rd10 Mice

Berkowitz

Podolsky

Berri

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeIn cyclic light-reared Pde6brd10 mice, rod cell oxidative stress contributes to the degenerative phenotype. Dark rearing Pde6brd10 mice slows but does not prevent atrophy. This suggests that outer retinal oxidative stress occurs in Pde6brd10 mice independent of light exposure, a hypothesis tested in this study.MethodsMouse strains Pde6brd10 and C57Bl/6 (wild type) were dark reared until postnatal day (P) 23 (P23) or P30. In subgroups of dark-reared mice, (1) layer-specific excessive free radical production (i.e., an oxidative stress biomarker) in vivo via QUEnch-assiSTed magnetic resonance imaging (QUEST MRI) was indicated by a significant reduction in the greater-than-normal spin-lattice relaxation rate R1 (1/T1) with methylene blue, (2) superoxide production was measured ex vivo in whole retina (lucigenin), and (3) retinal layer spacing and thickness were assessed in vivo (optical coherence tomography, MRI).ResultsIn P23 male Pde6brd10 mice, only the outer superior retina showed oxidative stress in vivo, as measured by QUEST MRI; a lucigenin assay confirmed supernormal superoxide production. In contrast, at P30, no evidence for retinal oxidative stress was observed. In P23 female Pde6brd10 mice, no retinal oxidative stress was apparent; however, at P30, oxidative stress was observed in superior inner and outer nuclear layers. Male and female Pde6brd10 mice at P23 had normal retinal thicknesses, whereas at P30, modest thinning was noted in inferior and superior retina.ConclusionsWe confirmed that outer retinal oxidative stress occurs in male and female dark-reared Pde6brd10 mice. Male and female Pde6brd10 mice demonstrated similar degrees of retinal thinning, but with unexpectedly distinct spatial and temporal retinal oxidative stress patterns.

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“…The experiment setup is crucial at this stage of the project for several reasons. First, the kinetics of degeneration of photoreceptors in the rd10 mouse is influenced by light [166]. To avoid any artifactual differences between the individually-treated animals, all the mice should be exposed to the same quantity of light over the entire duration of the experiment.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Clérin

Marussig

Sahel

et al. 2020

IJMS

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The loss of cone photoreceptor function in retinitis pigmentosa (RP) severely impacts the central and daily vision and quality of life of patients affected by this disease. The loss of cones follows the degeneration of rods, in a manner independent of the causing mutations in numerous genes associated with RP. We have explored this phenomenon and proposed that the loss of rods triggers a reduction in the expression of rod-derived cone viability factor (RdCVF) encoded by the nucleoredoxin-like 1 (NXNL1) gene which interrupts the metabolic and redox signaling between rods and cones. After providing scientific evidence supporting this mechanism, we propose a way to restore this lost signaling and prevent the cone vision loss in animal models of RP. We also explain how we could restore this signaling to prevent cone vision loss in animal models of the disease and how we plan to apply this therapeutic strategy by the administration of both products of NXNL1 encoding the trophic factor RdCVF and the thioredoxin enzyme RdCVFL using an adeno-associated viral vector. We describe in detail all the steps of this translational program, from the design of the drug, its production, biological validation, and analytical and preclinical qualification required for a future clinical trial that would, if successful, provide a treatment for this incurable disease.

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Dark-Rearing the rd10 Mouse: Implications for Therapy

Cited by 23 publications

References 18 publications

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx

Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6b^rd10 Mice

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

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Dark-Rearing the rd10 Mouse: Implications for Therapy

Cited by 23 publications

References 18 publications

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx

Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6brd10 Mice

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

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Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6b^rd10 Mice