The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia
| Autor: | Thomas Carell, Michael Stadlmeier, Mirja Koch, Xi-Qin Ding, Franziska R. Traube, Elisa Murenu, Andrea F. Glück, Hongwei Ma, Martin Biel, Fan Yang, Stylianos Michalakis, Constanze Scheel |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Achromatopsia genetic structures Fluorescent Antibody Technique Gene Expression Color Vision Defects lcsh:Chemistry Mice chemistry.chemical_compound 0302 clinical medicine cone photoreceptor Cyclic GMP lcsh:QH301-705.5 Spectroscopy Mice Knockout Microscopy Confocal Chemistry Retinal Degeneration General Medicine Endoplasmic Reticulum Stress Computer Science Applications Cell biology Second messenger system Retinal Cone Photoreceptor Cells neuroprotection Disease Susceptibility achromatopsia Programmed cell death Protein subunit Cyclic Nucleotide-Gated Cation Channels Cyclic GMP-Dependent Protein Kinase Type II Models Biological Article Catalysis Inorganic Chemistry 03 medical and health sciences medicine Animals Physical and Theoretical Chemistry Protein kinase A Molecular Biology Cyclic guanosine monophosphate photoreceptor degeneration cGMP cytotoxicity Endoplasmic reticulum Organic Chemistry medicine.disease Disease Models Animal 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Unfolded Protein Response 030221 ophthalmology & optometry Unfolded protein response sense organs Biomarkers |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 1 International Journal of Molecular Sciences, Vol 22, Iss 52, p 52 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22010052 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |