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Shreyasi Choudhury, Marina S. Gorbatyuk; Role of ER Stress-Induced Caspase7 in Retinal Degeneration of T17M Rhodopsin Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6446.
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The T17M mutation within the rhodopsin gene (RHO) causes protein misfolding, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response leading to autosomal dominant retinitis pigmentosa (ADRP). The ADRP photoreceptor cell death is known to occur through apoptosis and activation of caspases. Previous studies have shown that Casp-12 and Casp-7 are activated under ER stress conditions in ADRP animal models. Therefore, the goal of this study is to validate the UPR downstream marker, Casp-7 as a new therapeutic target for T17MRho retina. This therapeutic approach aimed to reduce ER stress-associated apoptosis could be used in the advanced stages of the ADRP alone or in combination with the therapy designed to reduce misfolded rhodopsin.
T17MRho Casp7-/-, T17MRho Casp7+/+, Casp7-/- and Casp7+/+(C57Bl/6) mice were used in the study. All groups were subjected to Electroretinogram (ERG) and Spectral Domain Optical Coherence Tomography (SD-OCT) analysis at postnatal (P) day 30, P60 and P90 of retinal degeneration. RNA was extracted from C57BL/6 and T17M Rho retina at P12, P15, P18, and P25 to perform qRT-PCR analysis of the Casp-7 gene expression.
Analysis of qRT-PCR demonstrated that the Casp-7 is significantly upregulated in T17MRho retina at P18, P21 and P25 compared to C57BL/6. Analysis of the scotopic ERG response demonstrated that the a- and b-wave amplitudes were significantly increased in T17MRho retina deficient in Casp-7 by 175%, 267%, 487% and 139%, 191%, 232% , correspondingly at P30, P60 and P90 compared to T17MRho Casp7+/+. The thickness of the Outer Nuclear Layer in T17M+/-Casp7-/- mice measured by SD-OCT was dramatically increased by 169%, 258% and 345% at P30, P60 and P90 correspondingly compared to T17M, Casp7+/+ mice.
Casp-7 deficiency leads to functional and structural preservation of T17MRho retina suggesting that the Casp-7 gene could be a viable therapeutic target for ADRP treatment.
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