The cell stress machinery and retinal degeneration

Abstract

a b s t r a c tRetinal degenerations are a group of clinically and genetically heterogeneous disorders characterised by progressive loss of vision due to neurodegeneration. The retina is a highly specialised tissue with a unique architecture and maintaining homeostasis in all the different retinal cell types is crucial for healthy vision. The retina can be exposed to a variety of environmental insults and stress, including light-induced damage, oxidative stress and inherited mutations that can lead to protein misfolding. Within retinal cells there are different mechanisms to cope with disturbances in proteostasis, such as the heat shock response, the unfolded protein response and autophagy. In this review, we discuss the multiple responses of the retina to different types of stress involved in retinal degenerations, such as retinitis pigmentosa, age-related macular degeneration and glaucoma. Understanding the mechanisms that maintain and re-establish proteostasis in the retina is important for developing new therapeutic approaches to fight blindness.

Inherent Instability of the Retinitis Pigmentosa P23H Mutant Opsin

“…Therefore, the 9-cis-retinal, which stabilizes P23H opsin, could be needed to treat P23H adRP. Other than supplemental chromophore analogs, new pharmacological chaperones are needed to test whether alleviating UPR (4,63,64) and/or proteasome overload (65) can rescue P23H adRP.…”

“…2 is a progressive retinal degenerative disease caused by heterogeneous genetic defects that affect more than a million people worldwide (1)(2)(3)(4). The disease is characterized by night blindness and progressive loss of peripheral vision due to rod photoreceptor cell death.…”

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

“…Further, the Met-450 variant of RPE65 expressed in C57/B6 mice is less active and slows the kinetics of rhodopsin regeneration by 4-fold when compared with the Leu-450 variant expressed by BALB/c mice (22). Thus the difference in the levels of R* generated by the same light exposure to BALB/c and C57 mice can be Ն400-fold, making the albino BALB/c mice an ideal light damage model to isolate the toxic effect of excessive R*, which generates reactive oxygen species and cause oxidative stress (2,24).…”

“…We showed that prolonged G-protein signaling caused by the lack of ARR1 led to a rapid induction of the PERK arm of the unfolded protein response (UPR) 2 followed by a coordinated increase in global protein ubiquitination and degradation of PDE6 and guanylyl cyclase activating protein 2 (GCAP2). These changes were prevented when G-protein signaling was abolished in the GNAT1 Ϫ/Ϫ background.…”

The Protective Effect of Erythropoietin on the Retina

“…Degeneration occurs in several chronic retinopathies including glaucoma, DR, age-related macular degeneration, and retinitis pigmentosa [27,28]. However, there is currently no cure for degenerative retinal diseases.…”