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Arjun Thapa, Lynsie Morris, Jianhua Xu, Stylianos Michalakis, Martin Biel, Xi-Qin Ding; Endoplasmic Reticulum Stress-associated Cone Degeneration in Cyclic Nucleotide-gated Channel Deficiency. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4282.
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Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with cone dystrophies and account for over 70% of all known cases of achromatopsia. Cones degenerate in achromatopsia and cone dystrophy patients and in CNGA3-/- and CNGB3-/- mice. This work investigates the molecular basis of cone degeneration resulting from CNG channel deficiency.
As cones comprise only 3-5% of the total photoreceptor population in a wild-type mouse retina, we generated the 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, cone degeneration and cell death, and opsin mislocalization as in their respective single knockout mice. The significant elevations of the endoplasmic reticulum stress markers, including Grp78/BiP, phospho-eIF2α, phospho-IP3R and CHOP, were detected in the retinas of CNGA3-/-/Nrl-/- and CNGB3-/-/Nrl-/- mice, compared to the age-matched Nrl-/- mice (at postnatal 30 days). Along with these findings, up-regulation of the cysteine protease calpains and cleavage of caspase-7 and caspase-12 were observed in the CNGA3-/-/Nrl-/- and CNGB3-/-/Nrl-/- retinas, suggesting an ER stress-associated apoptosis. In addition, we observed a nucleus translocation of AIF and Endo G in the channel-deficient retina, implying a mitochondrial insult in the ER stress-activated cell death process.
By using CNGA3-/-/Nrl-/- and CNGB3-/-/Nrl-/- mouse lines we demonstrate a primary role of the ER stress in cone degeneration in CNG channel deficiency.
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