Modulation of the rate of retinal degeneration in T17M RHO mice by reprogramming the unfolded protein response
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Updated: May 1, 2026
A Protocol to Evaluate and Quantify Retinal Pigmented Epithelium Pathologies in Mouse Models of Age-Related Macular Degeneration
Published on: March 10, 2023
Shreyasi Choudhury1, Sonali Nashine, Yogesh Bhootada
1Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, USA, shreyasi.choudhury@live.unthsc.edu.
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.
Insights
Targeting the unfolded protein response (UPR) by modulating caspase-7 shows promise for slowing retinal degeneration in ADRP mice. However, ablating CHOP protein unexpectedly worsened the condition, highlighting the complexity of UPR manipulation.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Autosomal dominant retinitis pigmentosa (ADRP) is a severe inherited retinal disease.
- The unfolded protein response (UPR) plays a critical role in cellular stress and has been implicated in retinal degeneration.
- Caspase-7 and CHOP proteins are key mediators in apoptotic pathways linked to UPR.
Purpose of the Study:
- To investigate the therapeutic potential of modulating UPR by targeting caspase-7 and CHOP proteins in ADRP mouse models.
- To determine the impact of caspase-7 and CHOP ablation on photoreceptor structure and function in T17M RHO mice.
Main Methods:
- Generation of T17M RHO CASP7 and T17M RHO CHOP mouse models.
- Assessment of retinal function using scotopic electroretinography (ERG).
- Evaluation of retinal structure via spectral-domain optical coherence tomography (SD-OCT) and histology.
- Analysis of protein expression using western blot.
Main Results:
- Scotopic ERG revealed significant preservation of photoreceptor function in T17M RHO mice with caspase-7 ablation.
- Conversely, CHOP protein ablation exacerbated retinal degeneration in T17M RHO mice.
- SD-OCT and histological data corroborated ERG findings, indicating UPR reprogramming influences degeneration rates.
- Caspase-7 ablation inhibited cJUN-mediated apoptosis, while CHOP ablation increased HDAC levels.
Conclusions:
- Modulating the UPR, specifically via caspase-7 inhibition, may offer a therapeutic strategy for ADRP.
- The role of CHOP in UPR-mediated retinal degeneration is complex and warrants further investigation.
- Careful examination of UPR manipulation is crucial for achieving therapeutic benefits in retinal diseases.
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