Genetic Background and Light-Dependent Progression of Photoreceptor Cell Degeneration in Prominin-1 Knockout Mice

Abstract

These findings improve our understanding of the mechanism of cell death in Prominin-1-related disease and provide evidence that fenretinide may be worth studying in human disease.

The Progression of the Stargardt Disease Type 4 (ProgStar-4) Study: Design and Baseline Characteristics (ProgStar-4 Report No. 1)

“…Indeed, ABCA4-related STGD1 shows elevated levels of lipofuscin-related autofluorescence intensity [25], and this facilitates the use of short-wavelength reduced autofluorescence imaging leading to comparable grading results with conventional FAF imaging [12]. Because photoreceptor cell degeneration of PROM1-knockout mice was shown to be light dependent based on histologic and functional examinations [26], we adopted this concept also for the ProgStar-4 study. However, we realized that a reduction of the laser power in PROM1-related disease may result in underexposed images and therefore the acquisition of an image with 25% laser power appeared not to be optimal for the ProgStar-4 study.…”

“…The study will permit a determination of structure-function correlations and longitudinal changes and deepen the understanding for the natural progression of STGD4. This is the first step towards possible therapies for PROM1-related maculopathies: As an example, administration of fenretinide, which lowers the level of the toxic lipofuscin, has been shown to slow down the degeneration of photoreceptor cells in Prom1 -/--knockout mice [26]. Other strategies such as reduction of oxidative stress [27] to slow down progression as well as restoration of sight by using optogenetics, stem cells or retinal prosthesis offer alternatives for future therapies [7].…”

Membrane Protrusion Formation Mediated by Rho/ROCK Signalling and Modulation of Chloride Flux

“…To address this question, we used mouse embryonic fibroblast (MEF) cells extracted from wild-type or Prom1 gene-deficient ( Prom1 knockout; Prom1 KO) embryos (10,26), and measured the temporal change of the intracellular chloride ion level upon calcium uptake by using the chloride-sensitive fluorescent indicator MQAE (N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide). As MQAE is quenched by chloride ion, the fluorescein intensity is reciprocal to the intracellular chloride ion concentration.…”

“…In pedigrees with mutations in the Prom1 gene, individuals carrying the homologous mutation suffer from inherited macular dystrophies termed as Stargardt’s disease and retinitis pigmentosa (RP); the symptoms begin in childhood, followed by gradual vision loss (7-9). In our previous study, we employed Prom1 gene deficient ( Prom1 KO) mice to demonstrate that photoreceptor degeneration occurs in response to light stimulation (10). In Prom1 KO mice, photoreceptor development and retinal structure at the perinatal stages are normal, but the membrane structure of the photoreceptor cells starts deforming once the eyes open (10).…”

“…In our previous study, we employed Prom1 gene deficient ( Prom1 KO) mice to demonstrate that photoreceptor degeneration occurs in response to light stimulation (10). In Prom1 KO mice, photoreceptor development and retinal structure at the perinatal stages are normal, but the membrane structure of the photoreceptor cells starts deforming once the eyes open (10). Nevertheless, as detailed molecular characterization of Prom1 is lacking, the underlying mechanisms for the initiation of retinal degeneration remain unclear.…”