Targeting Caspase-12 to Preserve Vision in Mice With Inherited Retinal Degeneration

Bhootada, Yogesh; Choudhury, Shreyasi; Gully, Clark; Gorbatyuk, Marina S.

doi:10.1167/iovs.15-16924

Cited by 9 publications

(14 citation statements)

References 33 publications

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“…In support of this hypothesis, the UPR reduction due to knockdown of ATF4 in T17M mice correlates with normal levels of activated caspase-3/7 at P30. Perhaps, similar to targeting caspase-7 [ 1 ] and 12 [ 48 ], this approach is sufficient to delay vision loss in T17M mice.…”

Section: Discussionmentioning

confidence: 99%

Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

et al. 2016

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T17M rhodopsin expression in rod photoreceptors leads to severe retinal degeneration and is associated with the activation of ER stress related Unfolded Protein Response (UPR) signaling. Here, we show a novel role of a UPR transcription factor, ATF4, in photoreceptor cellular pathology. We demonstrated a pro-death role for ATF4 overexpression during autosomal dominant retinitis pigmentosa (ADRP). Based on our results in ATF4 knockout mice and adeno-associated viral (AAV) delivery of ATF4 to the retina, we validated a novel therapeutic approach targeting ATF4 over the course of retinal degeneration. In T17M rhodopsin retinas, we observed ATF4 overexpression concomitantly with reduction of p62 and elevation of p53 levels. These molecular alterations, together with increased CHOP and caspase-3/7 activity, possibly contributed to the mechanism of photoreceptor cell loss. Conversely, ATF4 knockdown retarded retinal degeneration in 1-month-old T17M Rhodopsin mice and promoted photoreceptor survival, as measured by scotopic and photopic ERGs and photoreceptor nuclei row counts. Similarly, ATF4 knockdown also markedly delayed retinal degeneration in 3-month-old ADRP animals. This delay was accompanied by a dramatic decrease in UPR signaling, the launching of anti-oxidant defense, initiation of autophagy, and improvement of rhodopsin biosynthesis which together perhaps combat the cellular stress associated with T17M rhodopsin. Our data indicate that augmented ATF4 signals during retinal degeneration plays a cytotoxic role by triggering photoreceptor cell death. Future ADRP therapy regulating ATF4 expression can be developed to treat retinal degenerative disorders associated with activated UPR.

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Section: Discussionmentioning

confidence: 99%

Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

et al. 2016

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“…However, the exact role PERK plays in the retina has not been carefully assessed because detecting phosphorylated PERK (p-PERK) in vivo has proven challenging with current methodology. Although p-PERK has not been detected in the retinas of mice with retinal degenration (RD), the activation of the UPR and ISR has been observed 3 , 10 , 11 . Interestingly, a recent study showed a 50% decrease in p-eIF2α in P23H rats following treatment with a PERK inhibitor 3 , but the correlation between the ISR and translation has not been explored in RD.…”

Section: Introductionmentioning

confidence: 99%

Translational attenuation and retinal degeneration in mice with an active integrated stress response

2018

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An integrated stress response (ISR), identified in several different animal models of inherited retinal degeneration (IRD), is activated following various cellular stresses. The ISR results in the phosphorylation of eIF2α (p-eIF2α) and a consequent halt in protein synthesis. Although generally protective, persistent elevations in p-eIF2α could lead to cell demise. Therefore, we aimed to determine whether ISR activation is associated with diminished translation rates in mice with IRD. Retinal protein extracts from rd16 mice at different time points were analyzed and the retinal levels of protein synthesis were assessed using the SUnSET method. We found that rd16 mice experience persistent ISR activation: p-eIF2α, ATF4, and CHOP were significantly upregulated at P15 and P20. In agreement with ISR activation, we found that rd16 mice experience translational attenuation at P15. Similar to rd16, other IRD models, T17M RHO, and rd10 also demonstrated a decline in protein synthesis, correlating with p-eIF2α elevation. We then assessed the role of PERK and eIF2α in translational attenuation in rd16 using a PERK inhibitor, GSK2606414. We found that while the treatment significantly reduced p-eIF2α, it did not cause a complete recovery in translation. This suggests that eIF2α is not the only or even the primary point of translational control in IRD, and a second node of translational regulation comprising AKT and mTOR should be evaluated. Surprisingly, we found that AKT-mTOR signaling was diminished in rd16 and rd10 retinas, suggesting a potential link between AKT-mTOR and translational inhibition. Therefore, for the first time, this study shows translation attenuation in IRD models, and highlights the potential roles of eIF2α kinases and AKT-mTOR signaling that could grant valuable insight into the potential treatments for IRD.

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“…The pathological mechanisms involved in rod photoreceptor cell death in degenerating retinas include, but are not limited to, activation of the Unfolded Protein Response (UPR) [4–6], inflammatory signaling [4,7–9], and oxidative stress, [10,11] eventually resulting in both apoptotic and non-apoptotic cell death [12–15]. Expression of human mutant T17M rhodopsin (T17M) in mouse rods results in severe retinal degeneration that mimics human adRP.…”

Section: Introductionmentioning

confidence: 99%

“…Expression of human mutant T17M rhodopsin (T17M) in mouse rods results in severe retinal degeneration that mimics human adRP. The UPR or ER stress response is activated beginning at postnatal day 15 (P15) [16] and is involved in retinal degeneration in these mice [4], together with calpain-activated pathway [15,17] and inflammation [4]. Recent studies have highlighted the activation of microglia in the RP retina preceding photoreceptor cell death.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to metabolic instability in RP retinas, a recent study has demonstrated involvement of the pro-inflammatory TNFa cytokine [14,15,23,24] and the TNF receptor-associated factor (TRAF2) [10,13], which may facilitate apoptotic rod cell death in the T17M retina through activation of the c-Jun N-terminal kinase (JNK)/c-Jun. A number of studies have supported a contribution of TNF receptors to cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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TNFa knockdown in the retina promotes cone survival in a mouse model of autosomal dominant retinitis pigmentosa

Rana

Kotla

Fullard

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Expression of T17M rhodopsin (T17M) in rods activates the Unfolded Protein Response (UPR) and leads to the development of autosomal dominant retinitis pigmentosa (adRP). The rod death occurs in adRP retinas prior to cone photoreceptor death, so the mechanism by which cone photoreceptors die remains unclear. Therefore, the goal of the study was to verify whether UPR in rods induces TNFa-mediated signaling to the cones and to determine whether the TNFa deficit could prevent adRP cone cell death. Primary rod photoreceptors and cone-derived 661Wcells transfected with siRNA against TNFa were treated with tunicamycin to mimic activation of UPR in T17M retinas expressing normal and reduced TNFa levels. The 661W cells were then exposed to recombinant TNFa to evaluate cell viability. In vivo, the role of TNFa was assessed in T17M TNFa+/− mice by electroretinography, optical coherence tomography, histology, immunohistochemistry, and a cytokine enzyme-linked immunosorbent assay. Rods overexpressed and secreted TNFa in response to UPR activation. The recombinant TNFa treatment lowered the number of viable cones, inducing cell death through elevation of pro-inflammatory cytokines and caspase-3/7 activity. The TNFa deficiency significantly protected adRP retinas. The photopic ERG amplitudes and the number of surviving cones dramatically increased in T17M TNFa+/− mice. This neuroprotection was associated with a reduced level of pro-inflammatory cytokines. Our results indicate that rod photoreceptors, following UPR activation during adRP progression, secrete TNFa and signal a self-destructive program to the cones, resulting in their cell death. TNFa therefore holds promise as a therapeutic target for treatment of adRP.

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Targeting Caspase-12 to Preserve Vision in Mice With Inherited Retinal Degeneration

Cited by 9 publications

References 33 publications

Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

Translational attenuation and retinal degeneration in mice with an active integrated stress response

TNFa knockdown in the retina promotes cone survival in a mouse model of autosomal dominant retinitis pigmentosa

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