Advisory Committee Chair
Marina S Gorbatyuk
Advisory Committee Members
Bradley K Yoder
Steven J Pittler
Alecia K Gross
Timothy W Kraft
Document Type
Dissertation
Date of Award
2019
Degree Name by School
Doctor of Philosophy (PhD) School of Optometry
Abstract
Inherited retinal degeneration is a class of diseases in which there is no cure and very few treatment options available. An activated unfolded protein response has been detected in various animal models of retinal degenerative diseases. Several groups have found heightened activation of one pathway of the unfolded protein response in particular, the protein kinase R-like endoplasmic reticulum kinase signaling cascade, which converges on and phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to transiently halt protein synthesis and allow the cell to reestablish homeostasis. Although it is widely accepted that this signaling is inherently protective, hyperactivity or prolonged activation of this signaling can lead to cell demise. However, exactly what impact this signaling has on retinal degeneration is a topic that has not been adequately assessed. First, we found that the unfolded protein response was active in a mouse model of Leber congenital amaurosis, rd16, which coincided with a decrease in protein synthesis rates. Next, using pharmacological and genetic approaches, we demonstrate that the reduced protein synthesis rates seen in retinal degeneration are likely not a cell defense mechanism in degenerating retinas but may play a role in retinal pathogenesis. We provide evidence supporting restoration of protein synthesis as a means to delay retinal degeneration. We next assessed the role of eIF2α in retinal degeneration by genetically modulating a kinase, PERK, and a protein phosphatase 1 regulatory subunit, GADD34, responsible for eIF2α regulation in rd16 mice. Lowering phospho-eIF2α levels in the photoreceptors of rd16 mice was not sufficient to significantly elevate protein synthesis rates and had no impact on retinal degeneration. Elevating phospho-eIF2α levels by knocking out Gadd34 did not result in a significant change in retinal protein synthesis rates, but retinal degeneration was delayed in rd16 Gadd34-/- mice, indicating that the loss of Gadd34 may promote survival independently of its regulation of eIF2α phosphorylation. These studies demonstrate the reduced protein synthesis rates play a never before appreciated role in the progression of retinal degeneration. In addition, despite previous postulations, eIF2α phosphorylation may not play a significant role in retinal degeneration.
Recommended Citation
Starr, Christopher Ryan, "The Role Of Protein Synthesis Attenuation And Eif2-Alpha Phosphorylation In Retinal Degeneration" (2019). All ETDs from UAB. 3027.
https://digitalcommons.library.uab.edu/etd-collection/3027