Newton Fay, Halachev Mihail, Nguyen Linda, McKie Lisa, Mill Pleasantine, Megaw Roly
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
Princess Alexandra Eye Pavilion, NHS Lothian, Edinburgh, EH3 9HA, UK.
Nat Commun. 2025 Apr 29;16(1):4024. doi: 10.1038/s41467-025-59165-8.
Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.
遗传性视网膜疾病（IRDs）是全球失明的主要原因之一。开发IRDs治疗方法的最大障碍之一是这些疾病的异质性，已在超过280个基因中鉴定出致病突变。因此，找到适用于多种遗传病因的疗法是当务之急。要做到这一点，需要更深入地了解导致IRDs中光感受器死亡的常见或重叠分子途径以及它们汇聚的分子过程。在这里，我们在IRDs人源化小鼠模型中，表征了不同细胞死亡机制在整个疾病进展过程中对光感受器退化和丧失的作用。通过单细胞转录组学，我们确定了退化光感受器中的常见转录特征。此外，我们表明，在基因和功能不同的IRD模型中，自噬和线粒体损伤存在常见的早期缺陷，在疾病后期通过坏死性凋亡触发光感受器细胞死亡。这些结果表明，无论潜在的遗传病因如何，这些途径可能导致IRDs中的细胞死亡。这些见解为适用于大多数患者的IRDs新型、基因非特异性治疗提供了潜在的治疗靶点。
