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

Abstract

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.

Delineating the role of eIF2α in retinal degeneration

“…There are no known roles of eIF2α other than protein synthesis regulation, so it has been assumed that its phosphorylation leads to a substantial attenuation in protein synthesis rates, but no study has functionally and genetically modulated p-eIF2α in degenerating retinas and subsequently assessed retinal protein synthesis rates and photoreceptor survival. In addition, as we have proposed previously 1 , eIF2α may not be the primary point of translational control in degenerating retinas. Those findings make us question what role, if any, eIF2α phosphorylation plays in retinal degeneration.…”

“…Inherited retinal degeneration (IRD) is a class of retinal dystrophies in which there is currently no cure and few treatment options available. Activation of the unfolded protein response (UPR) has been detected in multiple animal models of retinal degeneration 1–5 . The UPR is a series of signaling events following endoplasmic reticulum (ER) stress and is signaled through three ER – resident membrane proteins, protein kinase R like-endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6).…”

In vivo phenotypic and molecular characterization of retinal degeneration in mouse models of three ciliopathies

“…Our results showed that, associated to Rhodopsin trafficking defect, key components of the ER stress response were upregulated on the transcriptional level that depicts a common mechanism linked to retinal degeneration in BBS syndromes and LCA, the Bbs1 M390R/M390R mice, Bbs10 −/− mice and Cep290 −/− mice models used herein; although further studies are required to verify this impact on the post-transcriptional level. These mechanisms were also present in Bbs12 −/− mice model, in the Rd16 mouse model; a LCA mice model (Mockel et al, 2012;Starr et al, 2018). In Bbs4 −/− mice models ER stress has not been reported to date even though a Rhodopsin trafficking is already known (Abd-El- Barr et al, 2007).…”

“…One of the commonly associated mechanism to photoreceptor apoptosis in the ciliopathies is a defective intraflagellar transport (IFT) of proteins between the two segments (Wright et al, 2010). This defect ultimately causes protein accumulation in the IS, which in turn triggers a proapoptotic unfolded protein response (UPR) associated with an ER-stress (Mockel et al, 2012;Starr et al, 2018). Previously, we have proved that UPR activation occurs in a Bbs12 model, leading us to develop a pharmacological approach (GIVin).…”

Lutein and Zeaxanthin Isomers Reduce Photoreceptor Degeneration in the Pde6brd10 Mouse Model of Retinitis Pigmentosa

“…We previously showed that L-Z ameliorated the ERS in the protection against light-induced retinopathy [34]. The rd10 mouse is a RP model with clear characteristics [35–38], which carries a missense point mutation in exon 13 of the rod phosphodiesterase 6B ( Pde6b ) gene [36, 37]. The mutations in the same gene also cause human RP [39, 40].…”