| First Author | Starr CR | Year | 2018 |
| Journal | Cell Death Dis | Volume | 9 |
| Issue | 5 | Pages | 484 |
| PubMed ID | 29706649 | Mgi Jnum | J:280324 |
| Mgi Id | MGI:6368362 | Doi | 10.1038/s41419-018-0513-1 |
| Citation | Starr CR, et al. (2018) Translational attenuation and retinal degeneration in mice with an active integrated stress response. Cell Death Dis 9(5):484 |
| abstractText | 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 eIF2alpha (p-eIF2alpha) and a consequent halt in protein synthesis. Although generally protective, persistent elevations in p-eIF2alpha 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-eIF2alpha, 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-eIF2alpha elevation. We then assessed the role of PERK and eIF2alpha in translational attenuation in rd16 using a PERK inhibitor, GSK2606414. We found that while the treatment significantly reduced p-eIF2alpha, it did not cause a complete recovery in translation. This suggests that eIF2alpha 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 eIF2alpha kinases and AKT-mTOR signaling that could grant valuable insight into the potential treatments for IRD. |
