Comparative single-cell analysis of multiple models of retinitis pigmentosa reveals common pro-survival mechanisms activated in photoreceptors

ABSTRACT: Retinitis pigmentosa (RP) is a group of inherited retinal diseases marked by the progressive degeneration of photoreceptors, ultimately leading to severe vision loss or blindness. The vast genetic heterogeneity of RP results in highly variable disease phenotypes, yet the identification of shared, mutation-independent mechanisms could provide a foundation for broadly applicable therapeutic strategies. To explore such mechanisms, we generated scRNA-seq datasets across three key timepoints in two RP mouse models, rd10 and P347S, and integrated them with public datasets from rd1 and AdipoR1-KO models. Time-course differential expression and gene regulatory network analyses revealed a conserved transcriptional response to retinal degeneration across photoreceptor types and disease models. Transcription factors such as Cebpd, Stat3, and E2f6 emerged as central regulators, consistently upregulated and potentially mediating pro-survival mechanisms. IEGs like Junb, Fosb, and Egr1 were consistently activated, configuring an early response to stress associated to apoptotic responses. Furthermore, we identified epigenetic regulators such as Dnmt1 and Atf7 upregulated across models, pointing to a role for chromatin remodeling in retinal degeneration. These findings support the existence of a core stress-induced regulatory program in RP and highlight promising targets for the development of mutation-independent, disease-modifying therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE296646 | GEO | 2026/07/31

REPOSITORIES: GEO