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Article

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

1
Department of Pharmacy—Center for Drug Research, Ludwig-Maximilians-University, 81377 Munich, Germany
2
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
3
Department of Chemistry, Ludwig-Maximilians-University, 81377 Munich, Germany
4
Department of Ophthalmology, Ludwig-Maximilians-University, 80336 Munich, Germany
*
Author to whom correspondence should be addressed.
Present affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ 08544, USA.
Int. J. Mol. Sci. 2021, 22(1), 52; https://doi.org/10.3390/ijms22010052
Received: 23 November 2020 / Revised: 18 December 2020 / Accepted: 19 December 2020 / Published: 23 December 2020
(This article belongs to the Special Issue Inherited Retinal Diseases)
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. View Full-Text
Keywords: achromatopsia; cone photoreceptor; cGMP cytotoxicity; photoreceptor degeneration; neuroprotection achromatopsia; cone photoreceptor; cGMP cytotoxicity; photoreceptor degeneration; neuroprotection
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MDPI and ACS Style

Koch, M.; Scheel, C.; Ma, H.; Yang, F.; Stadlmeier, M.; Glück, A.F.; Murenu, E.; Traube, F.R.; Carell, T.; Biel, M.; Ding, X.-Q.; Michalakis, S. The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia. Int. J. Mol. Sci. 2021, 22, 52. https://doi.org/10.3390/ijms22010052

AMA Style

Koch M, Scheel C, Ma H, Yang F, Stadlmeier M, Glück AF, Murenu E, Traube FR, Carell T, Biel M, Ding X-Q, Michalakis S. The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia. International Journal of Molecular Sciences. 2021; 22(1):52. https://doi.org/10.3390/ijms22010052

Chicago/Turabian Style

Koch, Mirja, Constanze Scheel, Hongwei Ma, Fan Yang, Michael Stadlmeier, Andrea F. Glück, Elisa Murenu, Franziska R. Traube, Thomas Carell, Martin Biel, Xi-Qin Ding, and Stylianos Michalakis. 2021. "The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia" International Journal of Molecular Sciences 22, no. 1: 52. https://doi.org/10.3390/ijms22010052

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