The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia
Mutations in the <i>CNGA3</i> 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,...
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/1/52 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mirja Koch |
| collection | DOAJ |
| description | Mutations in the <i>CNGA3</i> 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 <i>Cnga3</i> 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 <i>Cnga3</i> KO mice. Virus-mediated knockdown or genetic ablation of <i>Prkg2</i> in <i>Cnga3</i> 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 <i>Cnga3</i> 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. |
| first_indexed | 2024-03-10T13:50:16Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:50:16Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5193f53f75eb41f4ac95d6e5d79496b02023-11-21T02:12:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012215210.3390/ijms22010052The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of AchromatopsiaMirja Koch0Constanze Scheel1Hongwei Ma2Fan Yang3Michael Stadlmeier4Andrea F. Glück5Elisa Murenu6Franziska R. Traube7Thomas Carell8Martin Biel9Xi-Qin Ding10Stylianos Michalakis11Department of Pharmacy—Center for Drug Research, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Pharmacy—Center for Drug Research, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Chemistry, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Chemistry, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Pharmacy—Center for Drug Research, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Chemistry, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Chemistry, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Pharmacy—Center for Drug Research, Ludwig-Maximilians-University, 81377 Munich, GermanyDepartment of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Pharmacy—Center for Drug Research, Ludwig-Maximilians-University, 81377 Munich, GermanyMutations in the <i>CNGA3</i> 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 <i>Cnga3</i> 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 <i>Cnga3</i> KO mice. Virus-mediated knockdown or genetic ablation of <i>Prkg2</i> in <i>Cnga3</i> 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 <i>Cnga3</i> 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.https://www.mdpi.com/1422-0067/22/1/52achromatopsiacone photoreceptorcGMP cytotoxicityphotoreceptor degenerationneuroprotection |
| spellingShingle | 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 The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia International Journal of Molecular Sciences achromatopsia cone photoreceptor cGMP cytotoxicity photoreceptor degeneration neuroprotection |
| title | The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia |
| title_full | The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia |
| title_fullStr | The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia |
| title_full_unstemmed | The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia |
| title_short | The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the <i>Cnga3</i>-Deficient Mouse Model of Achromatopsia |
| title_sort | cgmp dependent protein kinase 2 contributes to cone photoreceptor degeneration in the i cnga3 i deficient mouse model of achromatopsia |
| topic | achromatopsia cone photoreceptor cGMP cytotoxicity photoreceptor degeneration neuroprotection |
| url | https://www.mdpi.com/1422-0067/22/1/52 |
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