Modulation of the rate of retinal degeneration in T17M RHO mice by reprogramming the unfolded protein response

Abstract

The goal of this study is to validate whether reprogramming of the UPR via modulation of pro-apoptotic caspase-7 and CHOP proteins could be an effective approach to slow down the rate of retinal degeneration in ADRP mice. In order to pursue our goal we created the T17M RHO CASP7 and T17M RHO CHOP mice to study the impact of the CASP7 or CHOP ablations in T17M RHO retina by ERG, SD-OCT, histology and western blot analysis. The scotopic ERG demonstrated that the ablation of the CASP7 in T17M RHO retina leads to significant preservation of the function of photoreceptors compared to control. Surprisingly, the ablation of pro-apoptotic CHOP protein in T17M RHO mice led to a more severe form of retinal degeneration. Results of the SD-OCT and histology were in agreement with the ERG data. The further analysis demonstrated that the preservation of the structure and function or the acceleration of the onset of the T17M RHO photoreceptor degeneration occurred via reprogramming of the UPR. In addition, the CASP7 ablation leads to the inhibition of cJUN mediated apoptosis, while the ablation of CHOP induces an increase in the HDAC. Thus, manipulation with the UPR requires careful examination in order to achieve a therapeutic effect.

Fig. 58.1

The lack of CSP7 and CHOP proteins modulates the vision loss in T17M photoreceptors. A: The a-wave of ERG amplitudes are modified in T17M CSP7 and T17M CHOP mice compared to control. B: The B-wave of ERG amplitudes are modified in T17M CSP7 and T17M CHOP mice compared to control. (*−P<0.05, **−P<0.01, ***−P<0.001, ****−P<0. 0001).

Fig. 58.2

The lack of CSP7 and CHOP proteins modifies the retinal structure and morphology in T17M mice. A and B: the average thickness of the ONL in the superior and inferior retinas correspondingly. C: The number of the nuclei measured by H&E histological analysis in the retina. D: Images of the H&E staining in the retina. (*−P<0.05, **−P<0.01, ***−P<0.001, ****−P<0. 0001).

Fig. 58.3

The UPR is modified in T17M retina deficient either in CSP7 or CHOP protein. A: The ATF4 and pATF6 protein are reduced in T17M retina deficient in CSP7. B: Increase in peIF2 and decreased in sXBP1 protein are found in T17M retina deficient in the CHOP. (*−P<0.05, **−P<0.01, ***−P<0.001).

Fig. 58.4

Modulation of the cellular signaling in T17M CSP7 and T17M CHOP mice. A: Modulation of the mTOR/pAKT signaling in T17M CSP7 retina. B: Modulation of the PAR1-TNFa-TRAF2-pcJUN pathways in T17M CSP7 retina. C: The HDAC and P300 protein expressions are modified in T17M CHOP retina. (*−P<0.05, **−P<0.01, ***−P<0.001, ****−P<0. 0001).