Abstract
The P23H mutation in rhodopsin (RhoP23H) 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 RhoP23H 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 RhoP23H 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.
Highlights
Retinitis pigmentosa (RP) is a group of inherited retinal diseases that are characterized by the degeneration of the retina
Our results show that in the presence of the RhoP23H transgene, the rate of decline in retinal sensitivity is similar in Chop or apoptosis signal-regulating kinase 1 (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
The Ask1 pathway has been implicated as a regulator of photoreceptor death in a transgenic RP mouse model expressing a RhoT17M mutation [38]. These findings suggest that unfolded protein response (UPR) genes may regulate photoreceptor death in RP, and regulating the ER stress response might be beneficial to the treatment of RP
Summary
Retinitis pigmentosa (RP) is a group of inherited retinal diseases that are characterized by the degeneration of the retina. Mutations in rhodopsin (Rho), the visual pigment of rod photoreceptors, accounts for ,10% of all cases of RP [1] These mutations have been grouped on the associated functional defects and cellular distribution of the protein [5]. In North America, the class II missense mutation P23H (RhoP23H), is the most common and accounts for .25% of all autosomal dominant forms of RP [4]. This mutation leads to a misfolded protein that is characterized by abnormal glycosylation pattern, abnormal disulfide bond formation and oligomerization [6]. The cellular mechanisms that lead to cell death are not completely understood
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