The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood, a problem that is exacerbated by the enormous genetic heterogeneity of this disease group. However, the last decade has yielded a wealth of new knowledge on degenerative pathways and their diversity. Notably, a central role of cGMP-signalling has surfaced for photoreceptor cell death triggered by a subset of disease-causing mutations.

In this review, we examine key aspects relevant for photoreceptor degeneration of hereditary origin. The topics covered include energy metabolism, epigenetics, protein quality control, as well as cGMP- and Ca²⁺-signalling, and how the related molecular and metabolic processes may trigger photoreceptor demise. We compare and integrate evidence on different cell death mechanisms that have been associated with photoreceptor degeneration, including apoptosis, necrosis, necroptosis, and PARthanatos. A special focus is then put on the mechanisms of cGMP-dependent cell death and how exceedingly high photoreceptor cGMP levels may cause activation of Ca²⁺-dependent calpain-type proteases, histone deacetylases and poly-ADP-ribose polymerase. An evaluation of the available literature reveals that a large group of patients suffering from hereditary photoreceptor degeneration carry mutations that are likely to trigger cGMP-dependent cell death, making this pathway a prime target for future therapy development.

Finally, an outlook is given into technological and methodological developments that will with time likely contribute to a comprehensive overview over the entire metabolic complexity of photoreceptor cell death. Building on such developments, new imaging technology and novel biomarkers may be used to develop clinical test strategies, that fully consider the genetic heterogeneity of hereditary retinal degenerations, in order to facilitate clinical testing of novel treatment approaches.

遗传性光感受器变性背后的细胞机制仍知之甚少，这一疾病群体的巨大遗传异质性加剧了这个问题。然而，最近十年产生了关于退化途径及其多样性的大量新知识。值得注意的是，cGMP信号传递的核心作用已经浮出水面，这些疾病是由一系列致病突变触发的感光细胞死亡。

在这篇综述中，我们研究了与遗传起源的光感受器变性有关的关键方面。涵盖的主题包括能量代谢，表观遗传学，蛋白质质量控​​制以及cGMP和Ca ²⁺信号传导，以及相关的分子和代谢过程如何触发光感受器死亡。我们比较并整合了与光感受器变性相关的不同细胞死亡机制的证据，包括细胞凋亡，坏死，坏死病和PARthanatos。然后特别关注cGMP依赖性细胞死亡的机制，以及过高的感光cGMP水平如何导致Ca ²⁺活化依赖性钙蛋白酶型蛋白酶，组蛋白脱乙酰基酶和聚ADP-核糖聚合酶。对现有文献的评估表明，患有遗传性光感受器变性的一大批患者携带可能触发cGMP依赖性细胞死亡的突变，从而使该途径成为未来治疗方法的主要目标。

最后，展望了技术和方法的发展，这些发展将随着时间的流逝而有助于对光感受器细胞死亡的整个代谢复杂性进行全面的概述。在这种发展的基础上，可以使用新的成像技术和新的生物标记物来开发临床测试策略，这些策略应充分考虑遗传性视网膜变性的遗传异质性，以便于对新的治疗方法进行临床测试。