Abstract
Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 account for >70% of all known cases of achromatopsia. Cones degenerate in achromatopsia patients and in CNGA3(-/-) and CNGB3(-/-) mice. This work investigates the molecular basis of cone degeneration in CNG channel deficiency. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice. The retinal phenotype and potential cell death pathways were examined by functional, biochemical, and immunohistochemical approaches. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice showed impaired cone function, opsin mislocalization, and cone degeneration similar to that in the single knock-out mice. The endoplasmic reticulum stress marker proteins, including Grp78/Bip, phospho-eIF2α, phospho-IP(3)R, and CCAAT/enhancer-binding protein homologous protein, were elevated significantly in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, compared with the age-matched (postnatal 30 days) Nrl(-/-) controls. Along with these, up-regulation of the cysteine protease calpains and cleavage of caspase-12 and caspase-7 were found in the channel-deficient retinas, suggesting an endoplasmic reticulum stress-associated apoptosis. In addition, we observed a nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, implying a mitochondrial insult in the endoplasmic reticulum stress-activated cell death process. Taken together, our findings suggest a crucial role of endoplasmic reticulum stress in cone degeneration associated with CNG channel deficiency.
Highlights
Photoreceptors undergo degeneration when phototransduction is impaired
The ERG responses for CNGA3Ϫ/Ϫ, CNGB3Ϫ/Ϫ, and wild-type are shown for comparison
No significant scotopic light response was detected in NrlϪ/Ϫ, CNGA3Ϫ/Ϫ/ NrlϪ/Ϫ, or CNGB3Ϫ/Ϫ/NrlϪ/Ϫ mice, due to Nrl deficiency
Summary
Results: The endoplasmic reticulum stress markers and processing of the associated caspases are elevated in retinas with cone photoreceptor CNG channel deficiency. As cones comprise only 2–3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3؊/؊/Nrl؊/؊ and CNGB3؊/؊/Nrl؊/؊ mice. Our findings suggest a crucial role of endoplasmic reticulum stress in cone degeneration associated with CNG channel deficiency. ER stress-associated photoreceptor death has been shown in animal models of retinitis pigmentosa, including those caused by mutations in rhodopsin (such as P23H mutation) [21, 22] and by deficiency of the rod phosphodiesterase (PDE6, rd mice) [20, 23]. ER stress might play a crucial role in cone degeneration in CNG channel deficiency
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