The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia.

Abstract

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

• Authors: Mirja Koch, Constanze Scheel, Hongwei Ma, Fan Yang, Michael Stadlmeier, Andrea F Glück, Elisa Murenu, Franziska R Traube, Thomas Carell, Martin Biel, Xi-Qin Ding, Stylianos Michalakis
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 1 (Dec 23 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33374621 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Cnga3 protein, mouse
• Cyclic Nucleotide-Gated Cation Channels
• Cyclic GMP-Dependent Protein Kinase Type II
• Cyclic GMP

Topics

• Animals
• Biomarkers
• Color Vision Defects (etiology, metabolism, pathology)
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinase Type II (genetics, metabolism)
• Cyclic Nucleotide-Gated Cation Channels (deficiency)
• Disease Models, Animal
• Disease Susceptibility
• Endoplasmic Reticulum Stress
• Fluorescent Antibody Technique
• Gene Expression
• Mice
• Mice, Knockout
• Microscopy, Confocal
• Models, Biological
• Retinal Cone Photoreceptor Cells (metabolism)
• Retinal Degeneration (etiology, metabolism, pathology)
• Unfolded Protein Response