| Author: | Cheng, Meng |
| Title: | Exploration of the role of OPN4 in a mouse model of retinal degeneration |
| Advisors: | Lin, Bin (SO) |
| Degree: | Ph.D. |
| Year: | 2023 |
| Subject: | Retinitis pigmentosa Eye -- Diseases Hong Kong Polytechnic University -- Dissertations |
| Department: | School of Optometry |
| Pages: | 1 volume (various pagings) : color illustrations |
| Language: | English |
| Abstract: | Retinitis pigmentosa (RP) is an inherited retinal degenerative disease (RD) that eventually ends with full blindness. Most pathogenic gene mutations affect the rod photoreceptors, leading to the primary death of rod photoreceptors followed by a subsequent loss of cone photoreceptors. Approximately 1 in 3,000 to 1 in 4,000 individuals are affected by RP in the world. This blind-causing retinopathy is genetically and clinically heterogeneous, so the definite pathogenic pathway of RP remains unclear. More importantly, there are still no effective therapies to halt the irreversible degeneration of rod and cone photoreceptors for RP till now. The main aim of this study was to explore the potential pathological mechanisms of RP. Melanopsin (OPN4) is an endogenous photosensitive protein found in the intrinsic photosensitive retinal ganglion cells (ipRGCs) and has been found as the strong reason for melanopsin expressing RGCs to various injuries. Therefore, we hypothesized that the ectopic expression of melanopsin in the retina could protect photoreceptors from death in RP mice. In the present study, we utilized rd10 mice, a popular mouse model of RP, which harbors mutations in the Pde6β gene of rod photoreceptors, Opn4-/-;rd10 mice and Opn4Cre/Cre; Rosa26 mice to observe the melanopsin expression in the retina and the impacts of melanopsin knock-out or overexpression on the normal retinas and the rd10 retinas. Firstly, we unexpectedly found that melanopsin was expressed in unexpected cone photoreceptors. However, the melanopsin ablation is considerably innocuous for the photoreceptor’s survival in normal retinas but appeared to largely exacerbate the photoreceptor’s death and aggravate vision impairment in rd10 retinas. By contrast, overexpressing melanopsin in rods, cones, or all photoreceptor cells with AAVs in rd10 mice and Opn4-/-;rd10 mice promote the photoreceptor’s survival and preserve visual function. There are numerous hypotheses underlying the pathological mechanism for photoreceptor loss in RP, while the accurate pathway remains obscure. Flow cytometry recovered that mitochondria dysfunction, ROS aberrant accumulation, and calcium (Ca2+) overload played a pathogenic role in the photoreceptor death in rd10 retinas, which can be reversed by melanopsin overexpression. Our proteomic analysis and western blot results demonstrated that CAMKII might contribute to the photoreceptor deficits in rd10 mice, which could be reversed by the overexpression of melanopsin. With the help of the intravitreal injection of CAMKII-specific inhibitor, KN93, we confirmed that both inhibiting CAMKII phosphorylation and overexpressing exogenous melanopsin can inhibit the activation of CREB. Therefore, we inferred that the CAMKII/CREB signaling plays a critical role in photoreceptor degeneration in rd10 mice and serves as a powerful therapeutic target that can be inhibited by melanopsin. Collectively, our study suggested that ectopic melanopsin overexpression in retinal cells could be a promising therapeutic strategy for photoreceptors protection in RP. |
| Rights: | All rights reserved |
| Access: | open access |
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