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In patients carrying the orthologous variant, the P23H rhodopsin knock-in mouse experiences retinal degeneration that mimics RP phenotype. In P23H-KI retinas, the P23H rhodopsin protein was degraded, and the Unfolded Protein Response promoted P23H rhodopsin degradation in heterologous cells in vitro, according to previous reports. In heterozygous P23H rhodopsin mice, we investigated the role of a UPR regulator gene, activating transcription factor 6, in rhodopsin protein homeostasis. In Atf6-/-Rho+/P23H retinas compared to Atf6+/-Rhodopsin protein enriched rhodopsin protein levels in early ages retinas, but not different mRNA values were found, though rhodopsin mRNA levels were not different.
Source link: https://doi.org/10.1038/s41598-021-95895-7
Rod photoreceptor degeneration has caused retinal disease and related retinal disorders, which necessitating therapeutics that promote rod photoreceptor survival. In a larval zebrafish model of inducible RP, we first conducted a large-scale phenotypic drug screen for drugs that promote rod cell growth. Leads were then tested in a series of mouse RP models in the hopes of finding compounds that were safe across species and RP models, i. e. potential pan-disease therapeutics. Nine of the 11 leads had neuroprotective effects in mouse primary photoreceptor cultures, and three of them promoted photoreceptor survival in mouse rd1 retinal explants, according to the three leads. In our zebrafish RP model, we reported parp1-dependent cell death via targeted cell death. According to both mice photoreceptor cultures and zebrafish, respectively, paired drug mixtures in mouse photoreceptor cultures and zebrafish showed improved and additive/synergistic neuroprotective properties. These findings show the effectiveness of cross-species/multi-model drug discovery, as well as the possibility of combinatorial drug therapy may have enhanced therapeutic benefits for RP patients.
Source link: https://doi.org/10.7554/eLife.57245
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