The UPR transducer—IRE1α—is required for photoreceptor health and protection against retinal degeneration

Abstract

Purpose : Several lines of evidence implicate the involvement of endoplasmic reticulum stress (ER stress) and its transducers in neurodegenerative diseases such as retinitis pigmentosa. ER stress triggers an intracellular signaling pathway called the Unfolded Protein Response (UPR). IRE1α is an ER resident protein that plays a major role in orchestrating the UPR. Here we aim to assess the contribution of IRE1α to photoreceptor homeostasis and retinal degeneration.

Methods : We selectively deleted IRE1α in rod photoreceptors of mice and investigated the physiological consequences in photoreceptor homeostasis and function. We also crossed these animals with the rhodopsin Rho^P23H mouse model of retinitis pigmentosa in order to evaluate the consequences of IRE1α loss in an in vivo setting of retinal degenerative disease. We assessed retinal thickness longitudinally using Optical Coherence Topography (OCT) and evaluated the retinal function by electroretinography (ERG) as animals aged.

Results : OCT imaging and histological analysis of IRE1α deficient mouse retinas did not reveal any abnormalities during early time points (1 and 3 months old). At 6 months and older however, the IRE1α deficient mice showed a progressive thinning of their outer nuclear layer (ONL) in the retina compared to the controls. ERG recordings during these later time points also showed decreased scotopic responses while photopic responses were unchanged. Analysis performed on IRE1α deficient mice on the rhodopsin Rho^P23H background revealed an exacerbated retinal degeneration in the absence of IRE1α.

Conclusions : These results suggest that IRE1α is dispensable for retinal development but important for maintaining photoreceptor homeostasis in aging retinas and for protecting against ER stress-related photoreceptor degeneration. Future work will establish whether there are compensatory changes in the other UPR pathways that could explain the lack of retinal phenotype observed during development.

This is a 2021 ARVO Annual Meeting abstract.