Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration.

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.

• Authors: S Choudhury, Y Bhootada, O Gorbatyuk, M Gorbatyuk
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e528 (Mar 07 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 23470535 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Small Interfering
• TNF Receptor-Associated Factor 2
• Rhodopsin
• Poly(ADP-ribose) Polymerases
• TOR Serine-Threonine Kinases
• JNK Mitogen-Activated Protein Kinases
• Caspase 7

Topics

• Animals
• Apoptosis
• Caspase 7 (chemistry, genetics, metabolism)
• Gene Expression
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Light
• Mice
• Mice, Transgenic
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Retina (metabolism, physiopathology, radiation effects)
• Retinal Degeneration
• Retinitis Pigmentosa (metabolism, physiopathology)
• Rhodopsin (metabolism)
• TNF Receptor-Associated Factor 2 (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Unfolded Protein Response