RT Journal Article
A1 Paquet-Durand, Francois
A1 Beck, Susanne
A1 Michalakis, Stylianos
A1 Goldmann, Tobias
A1 Huber, Gesine
A1 Mühlfriedel, Regine
A1 Becirovic, Elvir
A1 Wolfrum, Uwe
A1 Tanimoto, Naoyuki
A1 Seeliger, Mathias
T1  Genetic Ablation Of Rod Cyclic-nucleotide Gated (cng) Channels Rescues Rd1 Mouse Retinal Degeneration And Preserves Cone Photoreceptor Function
JF Investigative Ophthalmology & Visual Science
JO Invest. Ophthalmol. Vis. Sci.
YR 2011
VO 52
IS 14
SP 1806
OP 1806
SN 1552-5783
AB    Purpose:  The rd1 mouse is one of the most commonly studied animal models for retinitis pigmentosa (RP), a severe and frequently blinding human retinal degeneration. In several decades of research, the link between mutation-induced increase in photoreceptor cGMP levels and the extremely rapid cell death has remained poorly understood. Here, we set out to study the role of cyclic-nucleotide-gated (CNG) channels in the degenerative process, by crossing CNGb1-/- animals with rd1 mutant mice.     Methods:  Single mutant rd1 and CNGb1 animals as well as double mutant CNGb1-/- x rd1 animals were analysed using in vivo optic coherence tomography and scanning laser ophthalmoscopy imaging techniques, combined with electroretinographic functional testing. Ex vivo analysis included assessment of rod and cone photoreceptor markers, degenerative markers (calpain activity, TUNEL), cGMP contents, and electron microscopic ultrastructural analysis of rod outer segments.     Results:  In Cngb1-/- x rd1 double mutants devoid of regular CNG channels, cGMP levels were strongly elevated, but rod photoreceptor viability and outer segment morphology were greatly improved. Importantly, cone photoreceptors, the basis for high-resolution daylight and colour vision, survived and remained functional for extended periods of time.     Conclusions:  We demonstrated the major importance of CNG channels for rod photoreceptor loss supporting the hypothesis of deleterious calcium (Ca2+)-influx as a cause of rapid rod cell death. Furthermore, our results suggest that targeting rod CNG channels, rather than general Ca2+-channel blockade, is a promising symptomatic approach to treat otherwise incurable forms of cGMP-related RP.   
RD 5/8/2021