Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration.
Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration.
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DOI：
10.1038/cddis.2013.34
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发表时间：
2013-03-07
影响因子：
9
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在常染色体显性视网膜色素变性（ADRP）进展期间，在表达错误折叠的T17 M视紫红质（RHO）的小鼠视网膜中UPR被激活。因此，本研究的目的是验证UPR诱导的caspase-7作为一个新的治疗靶点，调节UPR，降低细胞凋亡水平，保护ADRP视网膜免受视网膜变性和光诱导的损伤。使用ERG、SD-OCT和组织学分析小鼠以确定半胱天冬酶-7消融的作用。这些实验的结果表明，与对照小鼠相比，从P30至P90，T17 M RHO CASP-7视网膜中的光感受器及其功能得到了显著的保留。这些小鼠也受到保护，免受光诱导的ERG反应和细胞凋亡的下降。T17 M RHO+ Csp 7-siRNA、Tn+ Csp 7-siRNA 661 W细胞和T17 M RHO CASP-7视网膜的RNA和蛋白质分析揭示，半胱天冬酶-7消融重新编程UPR并减少JNK诱导的细胞凋亡。这种减少被认为是通过下调mTOR和Hif 1a蛋白而发生的。此外，在T17 M RHO CASP-7视网膜中检测到活化PARP 1的下降。总之，我们的研究结果表明，在T17 M RHO小鼠中靶向caspase-7可能是晚期ADRP的可行治疗策略。
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.