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Updated: May 13, 2026
Quantification of Immunostained Caspase-9 in Retinal Tissue
Published on: July 25, 2022
Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal
S Choudhury1, Y Bhootada, O Gorbatyuk
1Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort-Worth, TX 76107, USA.
Abstract:
The UPR is activated in the mouse retina expressing misfolded T17M rhodopsin (RHO) during autosomal dominant retinitis pigmentosa (ADRP) progression. Therefore, the goal of this study is to validate the UPR-induced caspase-7 as a new therapeutic target that modulates the UPR, reduces the level of apoptosis and protects the ADRP retina from retinal degeneration and light-induced damage. Mice were analyzed using ERG, SD-OCT and histology to determine the role of caspase-7 ablation. The results of these experiments demonstrate the significant preservation of photoreceptors and their function in T17M RHO CASP-7 retinas from P30 to P90 compared with control mice. These mice were also protected from the light-induced decline in the ERG responses and apoptosis. The RNA and protein analyses of T17M RHO+Csp7-siRNA, Tn+Csp7-siRNA 661W cells and T17M RHO CASP-7 retinas revealed that caspase-7 ablation reprograms the UPR and reduces JNK-induced apoptosis. This reduction is believed to occur through the downregulation of the mTOR and Hif1a proteins. In addition, decline in activated PARP1 was detected in T17M RHO CASP-7 retina. Altogether, our findings indicate that the targeting of caspase-7 in T17M RHO mice could be a feasible therapeutic strategy for advanced stages of ADRP.
Insights
Targeting caspase-7 protects against retinal degeneration in autosomal dominant retinitis pigmentosa (ADRP). Ablating caspase-7 preserves photoreceptor function and reduces apoptosis in mouse models of ADRP.
Area of Science:
- Ophthalmology
- Cell Biology
- Genetics
Background:
- Autosomal dominant retinitis pigmentosa (ADRP) involves retinal degeneration.
- Misfolded T17M rhodopsin (RHO) activates the unfolded protein response (UPR) in ADRP.
- The UPR contributes to photoreceptor apoptosis and vision loss in ADRP.
Purpose of the Study:
- To investigate caspase-7 as a therapeutic target for ADRP.
- To determine if modulating the UPR via caspase-7 can protect the retina from degeneration.
- To assess the impact of caspase-7 ablation on apoptosis and light-induced damage in ADRP models.
Main Methods:
- Utilized mouse models expressing T17M RHO with and without caspase-7 ablation.
- Assessed retinal function using electroretinography (ERG).
- Evaluated retinal structure with spectral-domain optical coherence tomography (SD-OCT) and histology.
- Analyzed RNA and protein expression to understand molecular mechanisms.
Main Results:
- Caspase-7 ablation preserved photoreceptor structure and function in T17M RHO mice.
- Mice lacking caspase-7 showed protection against light-induced damage and apoptosis.
- Caspase-7 ablation reprogrammed the UPR, reducing JNK-induced apoptosis via mTOR and Hif1a downregulation.
Conclusions:
- Targeting caspase-7 is a potential therapeutic strategy for advanced ADRP.
- Caspase-7 inhibition mitigates UPR-associated retinal degeneration.
- This approach offers a novel way to protect the retina in ADRP.
