Delineating the role of eIF2α in retinal degeneration.

Activation of the unfolded protein response has been detected in various animal models of retinal degeneration. The PERK branch converges on eIF2α to regulate protein synthesis. We previously reported that diseased retinas produce less protein as they degenerate. We also proposed that the majority of this reduction in protein synthesis may not be due to control of eIF2α. Nevertheless, multiple research groups have reported that modulating eIF2α levels may be a viable strategy in the treatment of neurodegenerative diseases. Here, using two genetic approaches, a systemic Gadd34 knockout and a photoreceptor conditional Perk knockout, to alter p-eIF2α levels in rd16 mice, we demonstrate not only that degenerating retinas may not use this mechanism to signal for a decline in protein synthesis rates but also that modulation of p-eIF2α levels is insufficient to delay retinal degeneration.