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Sonali Nashine, Yogesh Bhootada, Alfred Lewin, Marina Gorbatyuk; Molecular mechanisms that contribute to vision loss in T17M RHO mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4194.
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© ARVO (1962-2015); The Authors (2016-present)
The T17M RHO transgenic mice carry a mutated human rhodopsin transgene, expression of which leads to protein misfolding, activation of the unfolded protein response (UPR) and progressive autosomal dominant retinitis pigmentosa (ADRP). Our previous study confirmed that the CHOP protein, a pro-apoptotic UPR marker, cannot be considered as a therapeutic target for ADRP photoreceptors expressing misfolded RHO. The purpose of this study is to determine the mechanism of accelerated retinal degeneration in T17M CHOP knock-out mice.
T17M RHO CHOP+/+ and T17M RHO CHOP-/- mice were recruited in this study. Protein extracts were isolated from retinas of one-month-old mice to perform western blotting and detect the level of p-eIF2α, XBP1, Rhodopsin, Histone deacetylase1 and P300 proteins.
An 8-fold increase of p-eIF2α (PERK pathway) in T17M RHO CHOP-/- retina compared to T17M RHO retina (0.5 ± 0.1 arbitrary units (a.u.) vs. 0.04 ± 0.1 a.u., P=0.01) was observed. The level of spliced Xbp1 (IRE1 pathway) in the T17M RHO retina was significantly reduced by 30% (0.6 ± 0.03 a.u vs 0.4 ± 0.03 a.u, P=0.004). The T17M RHO CHOP-/- retina was characterized by 78% reduction in the level of P300 protein compared to T17M RHO (0.3 ± 0.1 a.u vs. 0.1 ± 0.02 a.u.in, P=0.02). In contrast, the Hdac1 protein was significantly increased by 245% in T17M RHO CHOP-/- retinas compared to that in T17M RHO retina. The level of Hdac1 was 0.2 ± 0.05 a.u. in T17M RHO and 0.5 ± 0.1 a.u., in T17M RHO CHOP-/- (P=0.03).
The one -month old T17M CHOP-/- mouse retina mostly likely experiences a global transcriptional inhibition that leads to a reduction in the expression of photoreceptor-specific transcription factors (ARVO 2012). Increase in histone deacetylation and decrease in P300 protein suggests that the deacetylation process prevails in these mice.
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