Purchase this article with an account.
Lynsie Morris, Zihao Ma, Arjun Thapa, Hongwei Ma, Stylianos Michalakis, Martin Biel, Wolfgang Baehr, Xi-Qin Ding; Exploration of the Mechanisms of Cone Photoreceptor Death in the Deficiency of Phosphodiesterase. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5953.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Photoreceptor phosphodiesterase (PDE6) plays a pivotal role in phototransduction. Mutations in rod and cone PDE have been linked to human retinitis pigmentosa and achromatopsia/cone dystrophy. The cpfl1 mouse line, which has a naturally occurring mutation in the Pde6c gene, serves as a model to study the mechanism of cone degeneration. Deficiency of photoreceptor PDE prevents the breakdown of cGMP, the ligand of the cyclic nucleotide-gated (CNG) channel, and results in high levels of both cGMP and Ca2+ in the photoreceptors. In addition, mis-localization of cone opsin was observed in the retinas of cpfl1 mice. This work examined the potential role of these consequences in cone degeneration.
Both genetic and pharmacological methods were used to study retinal degeneration in cpfl1 mice. We generated two double knockout mouse lines, cpfl1/Cnga3-/- (Cnga3-/- mice lack the expression of cone CNG channel subunit CNGA3) and cpfl1/Gucy2e-/- (Gucy2e-/- mice lack the expression of retinal GC1) mice, to evaluate the effects of cGMP accumulation and high Ca2+ levels on cone death. The chemical chaperone tauroursodeoxycholic acid (TUDCA) was used to examine the role of opsin mis-localization and endoplasmic reticulum (ER) stress. Cone survival/death was evaluated by cone labeling using peanut agglutinin lectin (PNA) and anti-cone opsin and by examining expression levels of cone specific proteins.
Both cpfl1/Cnga3-/- mice, which lack the CNG channel-mediated calcium influx, and cpfl1/Gucy2e-/- mice, which lack GC1-mediated cGMP biosynthesis, showed significantly improved cone survival, demonstrated by increased cone density and expression levels of cone proteins when compared to age-matched cpfl1 mice. The cpfl1 line showed over 90% reduction in cone density, whereas both double knockout lines had around 65-70% reduction at 3 months of age. Treatment with TUDCA significantly reduced cone death in cpfl1 mice, suggesting a role of ER stress in cone degeneration in PDE deficiency.
Our results show that there are multiple mechanisms that underlie cone death in PDE deficiency and provide insights into potential targets for treatment in inherited cone degenerations.
This PDF is available to Subscribers Only