Ablation of the proapoptotic genes chop or Ask1 does not prevent or delay loss of visual function in a P23H transgenic mouse model of retinitis pigmentosa

The P23H mutation in rhodopsin (Rho^P23H) is a prevalent cause of autosomal dominant retinitis pigmentosa. We examined the role of the ER stress proteins, Chop and Ask1, in regulating the death of rod photoreceptors in a mouse line harboring the Rho^P23H rhodopsin transgene (GHL ⁺). We used knockout mice models to determine whether Chop and Ask1 regulate rod survival or retinal degeneration. Electrophysiological recordings showed similar retinal responses and sensitivities for GHL⁺, GHL ⁺ /Chop^-/- and GHL⁺ /Ask1^-/- animals between 4-28 weeks, by which time all three mouse lines exhibited severe loss of retinal function. Histologically, ablation of Chop and Ask1 did not rescue photoreceptor loss in young animals. However, in older mice, a regional protective effect was observed in the central retina of GHL⁺/ Chop^-/- and GHL⁺/Ask1^-/-, a region that was severely degenerated in GHL⁺ mice. Our results show that in the presence of the Rho^P23H transgene, the rate of decline in retinal sensitivity is similar in Chop or Ask1 ablated and wild-type retinas, suggesting that these proteins do not play a major role during the acute phase of photoreceptor loss in GHL⁺ mice. Instead they may be involved in regulating secondary pathological responses such as inflammation that are upregulated during later stages of disease progression.