{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T06:24:32Z","timestamp":1794551072922,"version":"4.9.1"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Retinitis Pigmentosa (RP) is the most common inherited retinal degeneration, characterized by an initial loss of rod photoreceptor cells. Photoreceptor cell death has been associated with high levels of cyclic guanosine-3\u2032, 5\u2032- monophosphate (cGMP) in animal models of autosomal recessive RP (ARRP) and autosomal dominant RP (ADRP). cGMP analogues inhibiting protein kinase G (PKG) have been found to prevent rod degeneration in ARRP disease models, but their effects on ADRP are unknown. Here, we used the recently generated rhodopsin-mutant\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/+<\/jats:sup>\n                    ADRP mouse model to study cGMP-signaling and the effects of cGMP analogues targeting PKG. cGMP accumulation was investigated by retinal immunostaining in wild-type (WT),\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/+<\/jats:sup>\n                    , and\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/I255d<\/jats:sup>\n                    mice. The therapeutic efficacy of the cGMP analogues CN03 and CN238 was evaluated on organotypic retinal explant cultures derived from WT and\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/+<\/jats:sup>\n                    mice. Readouts included the TUNEL assay and immunostaining for cone arrestin-3. Downstream effectors of cell death were visualized using calpain, poly-ADP-ribose polymerase (PARP), and histone deacetylase (HDAC) in situ assays, as well as caspase-3 immunostaining. Photoreceptor function was assessed using micro-electroretinogram (\u00b5ERG) recordings. When compared with WT,\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d<\/jats:sup>\n                    photoreceptors displayed cGMP accumulation in outer segments. In the\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/+<\/jats:sup>\n                    ADRP model, CN03 and CN238 significantly reduced the number of dying photoreceptors. However, the relatively small number of photoreceptors exhibiting caspase-3 activity was not changed by the treatment. Remarkably, CN238 effectively provided long-lasting neuroprotection of cone photoreceptors and preserved retinal light responsiveness of\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/+<\/jats:sup>\n                    retina. Overall, this study suggests caspase-independent but cGMP-dependent cell death as a dominant degenerative mechanism in the\n                    <jats:italic>Rho<\/jats:italic>\n                    <jats:sup>I255d\/+<\/jats:sup>\n                    ADRP mouse model. PKG inhibition demonstrated robust neuroprotection of both rod and cone photoreceptors, while the marked preservation of retinal function, especially with the compound CN238, highlighted cGMP analogues for the treatment of ADRP.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07901-9","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T04:28:43Z","timestamp":1753849723000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protein kinase G inhibition preserves photoreceptor viability and function in a new mouse model for autosomal dominant retinitis pigmentosa"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-1356","authenticated-orcid":false,"given":"Yu","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7136-5847","authenticated-orcid":false,"given":"Lucia","family":"Peiroten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5118-3060","authenticated-orcid":false,"given":"Pranav","family":"Nanda Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4156-7631","authenticated-orcid":false,"given":"Catherine","family":"Hottin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3202-5993","authenticated-orcid":false,"given":"Kangwei","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0890-9780","authenticated-orcid":false,"given":"Wadood","family":"Haq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7355-5742","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Paquet-Durand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"7901_CR1","doi-asserted-by":"publisher","first-page":"2909","DOI":"10.2147\/OPTH.S370032","volume":"16","author":"N Cross","year":"2022","unstructured":"Cross N, van Steen C, Zegaoui Y, Satherley A, Angelillo L. Current and future treatment of retinitis pigmentosa. Clin Ophthalmol. 2022;16:2909\u201321.","journal-title":"Clin Ophthalmol"},{"key":"7901_CR2","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1016\/S0140-6736(06)69740-7","volume":"368","author":"DT Hartong","year":"2006","unstructured":"Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368:1795\u2013809.","journal-title":"Lancet"},{"key":"7901_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.preteyeres.2017.10.002","volume":"62","author":"D Athanasiou","year":"2018","unstructured":"Athanasiou D, Aguila M, Bellingham J, Li W, McCulley C, Reeves PJ, et al. The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. 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Long-term, serum-free cultivation of organotypic mouse retina explants with intact retinal pigment epithelium. J Vis Exp. 2020;e61868. https:\/\/doi.org\/10.3791\/61868.","DOI":"10.3791\/61868"},{"key":"7901_CR42","doi-asserted-by":"publisher","first-page":"e0245369","DOI":"10.1371\/journal.pone.0245369","volume":"16","author":"S Belhadj","year":"2021","unstructured":"Belhadj S, Rentsch A, Schwede F, Paquet-Durand F. Fluorescent detection of PARP activity in unfixed tissue. PLoS One. 2021;16:e0245369.","journal-title":"PLoS One"},{"key":"7901_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/srep39537","volume":"6","author":"A Sahaboglu","year":"2016","unstructured":"Sahaboglu A, Barth M, Secer E, Amo EMD, Urtti A, Arsenijevic Y, et al. Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration. 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Mireca Medicines intends to promote cGMP analogues such as CN03 or CN238 for clinical testing in rare inherited diseases of the retina. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. The animal studies complied with the Association for Research in Vision and Ophthalmology (ARVO) statement for the use of animals in vision research, and the German law on animal protection was reviewed and approved by the \u201cEinrichtung fuer Tierschutz, Tier\u00e4rztlichen Dienst und Labortierkunde\u201d of the University of Tuebingen (Registration Nos: AK02\/20M; AK01\/22M).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"575"}}