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Retinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 ( Atf6 ), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin ( Rho  + /P23H  ) mice. Significantly increased rhodopsin protein levels were found in  Atf6   −/−   Rho  + /P23H   retinas compared to  Atf6  + /−   Rho  + /P23H   retinas at early ages (~ P12), while  rhodopsin  mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young  Atf6   −/−   Rho  + /P23H   retinas, and photoreceptor layer thickness was unchanged at this early age in  Rho  + /P23H   mice lacking  Atf6 . By contrast, older  Atf6   −/−   Rho  + /P23H   mice developed significantly increased retinal degeneration in comparison to  Atf6  + /−   Rho  + /P23H   mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that  Atf6  is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of  Atf6  ultimately accelerates retinal degeneration in P23H-KI mice.

ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model