June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Exploration of the Mechanisms of Cone Photoreceptor Death in the Deficiency of Phosphodiesterase
Author Affiliations & Notes
  • Lynsie Morris
    Cell Biology, OU Health Sciences Center, Oklahoma City, OK
  • Zihao Ma
    Cell Biology, OU Health Sciences Center, Oklahoma City, OK
  • Arjun Thapa
    Cell Biology, OU Health Sciences Center, Oklahoma City, OK
  • Hongwei Ma
    Cell Biology, OU Health Sciences Center, Oklahoma City, OK
  • Stylianos Michalakis
    Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany
  • Martin Biel
    Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany
  • Wolfgang Baehr
    John A. Moran Eye Center, University of Utah, Salt Lake City, UT
  • Xi-Qin Ding
    Cell Biology, OU Health Sciences Center, Oklahoma City, OK
  • Footnotes
    Commercial Relationships Lynsie Morris, None; Zihao Ma, None; Arjun Thapa, None; Hongwei Ma, None; Stylianos Michalakis, None; Martin Biel, None; Wolfgang Baehr, None; Xi-Qin Ding, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 5953. doi:
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      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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 695 retinal degenerations: cell biology • 648 photoreceptors  
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