Abstract
Photoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa, a rare disease typically diagnosed in adolescents and young adults. In most cases, rod loss occurs first, followed by cone loss as well as altered function in cells connected to photoreceptors directly or indirectly. There remains a gap in our understanding of retinal cellular responses to photoreceptor abnormalities. Here, we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in retinitis pigmentosa model (P23H) mice vs. wild-type littermate mice. We found a significant decrease in the expression of genes associated with phototransduction, the inner/outer segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. Accompanying this loss was a significant decrease in the expression of genes involved in metabolic pathways and energy production in both rods and cones. We found that in the Müller glia/astrocyte cluster, there was a significant increase in gene expression in pathways involving photoreceptor maintenance, while concomitant decreases were observed in rods and cones. Additionally, the expression of genes involved in mitochondrial localization and transport was increased in the Müller glia/astrocyte cluster. The Müller glial compensatory increase in the expression of genes downregulated in photoreceptors suggests that Müller glia adapt their transcriptome to support photoreceptors and could be thought of as general therapeutic targets to protect against retinal degeneration.
Highlights
Retinitis pigmentosa (RP) is a rare retinal disorder with photoreceptor loss, and most gene mutations (>150) associated with RP are in rods[1,2]
We found an ~35% decrease in outer nuclear layer (ONL) thickness and an ~30% decrease in the photoreceptor inner/outer segment (IS/OS) layer in P23H vs. WT mice (Fig. 1b), suggesting that photoreceptor degeneration occurs earlier than PW4
There was no significant change in the thickness of the inner nuclear layer (INL) or inner plexiform layer (IPL) (layer composed of synapses connecting inner neurons with retinal ganglion cells (RGCs); Fig. 1b)
Summary
Retinitis pigmentosa (RP) is a rare retinal disorder with photoreceptor (rod and cone) loss, and most gene mutations (>150) associated with RP are in rods[1,2]. If a common pathway contributing to photoreceptor degeneration could be targeted, retinal function might be maintained in all types of RP. We analyzed the gene profile of each major retinal cell type (rods, cones, bipolar cells, amacrine cells, and retinal glia (Müller glia/astrocytes)) using single-cell RNA-seq (scRNA-seq) in a RP model (P23H) mice. These mutant mice, which have an amino acid substitution of proline to histidine in codon 23 of rhodopsin (the most common mutation responsible for autosomal-dominant RP in the USA)[6], show decreased rod responses followed by reduced cone responses, similar to human patients[7]
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