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Yogesh Bhootada, Shreyasi Choudhury, Marina Gorbatyuk; Role of ER Stress-Induced Caspase12 in Retinal Degeneration of T17M RHO mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):650.
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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-7 is activated under ER stress conditions in ADRP animal models. Therefore, the goal of this study is to validate the UPR downstream marker, Casp-12 as a new therapeutic target for T17M RHO 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.
T17M RHO Casp-12-/-, T17M RHO Casp-12+/+, Casp-12-/- and Casp-12+/+ (C57Bl/6) mice were used in the study. All groups were subjected to electroretinogram (ERG) and spectral domain optical coherent tomography (SD-OCT) analysis at postnatal (P) day 30 and P90 of retinal degeneration. RNA was extracted from C57BL/6 and T17M RHO retina at P12, P18, P21, and P25 to perform qRT-PCR analysis of the Casp-12 gene expression
Analysis of qRT-PCR demonstrated that the Casp-12 is significantly up regulated in T17M RHO retina at P18, P21 and P25 by 3-4 fold compared to C57BL/6. Analysis of the scotopic ERG response demonstrated that the a- and b-wave amplitudes were significantly increased in T17M RHO retina deficient in Casp-12 by 222%, 669% and 154%, 232% , correspondingly at P30 and P90 compared to T17M RHO Casp-12+/+. The thickness of the Outer Nuclear Layer in superior and inferior regions of T17M RHO Casp12-/- mice measured by SD-OCT was dramatically increased by 132%,135% and 278%,317%, respectively at P30 and P90 as compared to T17M RHO Casp12+/+ mice
Casp-12 deficiency leads to functional and structural preservation of T17M RHO retina suggesting that the Casp-12 gene could be a viable therapeutic target for the treatment of ADRP
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