Phototoxicity avoidance is a potential therapeutic approach for retinal dystrophy caused by EYS dysfunction
Yuki Otsuka, Keiko Imamura, Akio Oishi, Kazuhide Asakawa, Takayuki Kondo, Risako Nakai, Mika Suga, Ikuyo Inoue, Yukako Sagara, Kayoko Tsukita, Kaori Teranaka, Yu Nishimura, Akira Watanabe, Kazuhiro Umeyama, Nanako Okushima, Kohnosuke Mitani, Hiroshi Nagashima, Koichi Kawakami, Keiko Muguruma, Akitaka Tsujikawa, Haruhisa Inoue
Yuki Otsuka, Keiko Imamura, Akio Oishi, Kazuhide Asakawa, Takayuki Kondo, Risako Nakai, Mika Suga, Ikuyo Inoue, Yukako Sagara, Kayoko Tsukita, Kaori Teranaka, Yu Nishimura, Akira Watanabe, Kazuhiro Umeyama, Nanako Okushima, Kohnosuke Mitani, Hiroshi Nagashima, Koichi Kawakami, Keiko Muguruma, Akitaka Tsujikawa, Haruhisa Inoue
View: Text | PDF
Research Article Ophthalmology Stem cells

Phototoxicity avoidance is a potential therapeutic approach for retinal dystrophy caused by EYS dysfunction

Abstract

Inherited retinal dystrophies (IRDs) are progressive diseases leading to vision loss. Mutation in the eyes shut homolog (EYS) gene is one of the most frequent causes of IRD. However, the mechanism of photoreceptor cell degeneration by mutant EYS has not been fully elucidated. Here, we generated retinal organoids from induced pluripotent stem cells (iPSCs) derived from patients with EYS-associated retinal dystrophy (EYS-RD). In photoreceptor cells of RD organoids, both EYS and G protein–coupled receptor kinase 7 (GRK7), one of the proteins handling phototoxicity, were not in the outer segment, where they are physiologically present. Furthermore, photoreceptor cells in RD organoids were vulnerable to light stimuli, and especially to blue light. Mislocalization of GRK7, which was also observed in eys-knockout zebrafish, was reversed by delivering control EYS into photoreceptor cells of RD organoids. These findings suggest that avoiding phototoxicity would be a potential therapeutic approach for EYS-RD.

Authors

Yuki Otsuka, Keiko Imamura, Akio Oishi, Kazuhide Asakawa, Takayuki Kondo, Risako Nakai, Mika Suga, Ikuyo Inoue, Yukako Sagara, Kayoko Tsukita, Kaori Teranaka, Yu Nishimura, Akira Watanabe, Kazuhiro Umeyama, Nanako Okushima, Kohnosuke Mitani, Hiroshi Nagashima, Koichi Kawakami, Keiko Muguruma, Akitaka Tsujikawa, Haruhisa Inoue

×

Figure 7

The effect of light wavelength on photoreceptor cell death in retinal organoids.

Options: View larger image (or click on image) Download as PowerPoint
The effect of light wavelength on photoreceptor cell death in retinal or...
(A) Retinal organoids were exposed to blue, green, or red LED light on day 180 for 24 hours. (B) The peak wavelengths of blue, green, and red lights were 454, 514, and 628 nm, respectively. (C) Representative immunofluorescence images of photoreceptor marker (ARR1) and cleaved caspase-3 (Cl. CASP3) in control and RD retinal organoids after exposure to each LED light. White arrowheads indicate cleaved caspase-3–positive cells. Scale bars: 50 μm. (D) Quantification of the data in C. The y axis indicates the number of cleaved caspase-3–positive cells per field. Data represent mean ± SEM from 3 retinal organoids. One-way ANOVA with Dunnett’s post hoc test was used for statistical comparison (*P < 0.05). (E) Schematic representation of putative mechanism of EYS-RD. EYS interacts with GRK7 and transports it from the IS to the OS. In control photoreceptor cells, EYS can localize at the CC and OS, whereas in RD, EYS with GRK7 cannot distribute to these regions. Light-induced damage via excessive reactive oxygen species production is caused by the mislocalization of mutant EYS with GRK7.