Retinitis Pigmentosa represents a group of genetic disorders that cause progressive vision loss via degeneration of photoreceptors, but there is in principle no treatment available. For any therapy development, a deeper comprehension of the disease-leading mechanism(s) at the molecular level is needed. Here we focused on the cGMP-PKG system, which has been suggested to be a driver in several models of the disease. To gain insights in its downstream signaling we manipulated the cGMP-PKG system with the aid of organotypic retinal explant cultures from either a mouse-based disease model, i.e. the rd1 mouse, or its healthy wild-type counterpart (wt), by adding different types of cGMP analogues to either inhibit or activate PKG in retinal explants from rd1 and wt, respectively. An RNA sequencing was then performed to study the cGMP-PKG dependent transcriptome. Expression changes of gene sets related to specific pathways or functions, that fulfilled criteria involving that the changes should match PKG activation and inhibition, were determined via bioinformatics. The analyses highlighted that several gene sets linked to oxidative phosphorylation and mitochondrial pathways were regulated by this enzyme system. Specifically, the expression of such pathway components was upregulated in the rd1 treated with PKG inhibitor and downregulated in the wt with PKG activator treatment, suggesting that cGMP-PKG act as a negative regulator in this context. Downregulation of energy production pathways may thus play an integral part in the mechanism behind the degeneration for at least several RP mutations.

色素性视网膜炎是一组通过光感受器退化导致进行性视力丧失的遗传性疾病，但原则上没有可用的治疗方法。对于任何疗法的开发，都需要在分子水平上更深入地了解疾病的主导机制。在这里，我们专注于 cGMP-PKG 系统，该系统已被建议作为多种疾病模型的驱动因素。为了获得在其下游信号的见解，我们操纵的cGMP-PKG系统无论是从基于鼠标的疾病模型，器官视网膜外植体培养的辅助即所述RD1鼠标，或它的健康的野生型对应物（重量）中，加入不同抑制或激活rd1视网膜外植体中 PKG 的 cGMP 类似物类型和重量分别。然后进行 RNA 测序以研究 cGMP-PKG 依赖性转录组。通过生物信息学确定与特定途径或功能相关的基因组的表达变化，满足涉及变化应与 PKG 激活和抑制相匹配的标准。分析强调，与氧化磷酸化和线粒体途径相关的几个基因组受该酶系统的调节。具体而言，此类通路成分的表达在rd1用PKG抑制剂处理并在用PKG激活剂处理的wt中下调，表明cGMP-PKG在这种情况下充当负调节剂。因此，能量产生途径的下调可能在至少几个 RP 突变的退化背后的机制中发挥不可或缺的作用。