SRP309656 PRJNA707351 Muller glial responses compensate for degenerating photoreceptors in retinitis pigmentosa Photoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa (RP), a rare disease typically diagnosed in adolescents and young adults. In most cases, rods loss occurs first, followed by cones, as well as altered function in cells connected to photoreceptors directly or indirectly. There is still a big knowledge gap in understanding retinal cellular responses to photoreceptor abnormalities. Here we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in mouse RP model (P23H) vs wild-type mice. We found that there was a significant decrease in genes involved in phototransduction, IS_OS segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone cluster, in line with their structural changes with immunohistochemistry. Accompanied with this loss, there was also a remarkable decrease in genes involved in metabolic pathways and energy production in both clusters. Furthermore, we found that in Muller glia and astrocytes cluster, there was a striking up-regulation in pathways responsible for photoreceptor maintenance, which were decreased in rods and cones. Additionally, genes involved in mitochondrion localization and transport were up-regulated in Muller glia and astrocytes cluster. Therefore, enhancing photoreceptor metabolism and modulating Muller glial responses may be general therapeutic approaches to protect against retinal degeneration.