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Review
. 2013 Jun 27;587(13):2008-17.
doi: 10.1016/j.febslet.2013.05.020. Epub 2013 May 15.

The cell stress machinery and retinal degeneration

Dimitra Athanasiou  1 , Monica Aguilà, Dalila Bevilacqua, Sergey S Novoselov, David A Parfitt, Michael E Cheetham
Affiliations
Review

The cell stress machinery and retinal degeneration

Dimitra Athanasiou et al. FEBS Lett. .

Abstract

Retinal 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.

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Figures

Figure 1
Figure 1. Structure of the mammalian retina
Schematic cross section representing the different cell types and layers of the retina. The choroid (CRD) containing red blood cells (RBCs) is found at the very back of the eye and is separated from the retinal pigmented epithelia (RPE) by the Bruch’s membrane (BM). The RPE extends microvilli (MV) that facilitate the interaction between the RPE and photoreceptors (PRs). Cone (CPR) and rod (RPR) photoreceptors contain the cone and rod outer and inner segments (COS, ROS and IS respectively), the outer nuclear layer (ONL) and outer plexiform layer (OPL), which contains the synapses of the photoreceptors, horizontal cells (HCs) and bipolar cells (BCs). The inner nuclear layer (INL) contains the cell bodies of the horizontal, bipolar and amacrine cells (AmCs). The inner plexiform layer (IPL) is formed of the connections between bipolar and amacrine cells to the retinal ganglion cells (RGCs), in the ganglion cell layer (GCL).
Figure 2
Figure 2. Photoreceptor proteostasis networks
Schematic showing the proteostasis networks in a rod photoreceptor that deal with misfolded proteins, such as P23H rod opsin (mutant rhodopsin in green), or cell stress. (A) ERAD. Misfolded proteins are detected by the ER quality control machinery (including BiP, EDEM1, VCP) and shuttled to the cytoplasm by the retrotranslocon where they are ubiquitylated before being degraded by the proteasome. (B) The UPR. Misfolded proteins, such as mutant rod opsin, in the ER are recognised by three sensors: IRE1, PERK and ATF6 that inhibit protein synthesis and stimulate the production of chaperones and the ERAD machinery (see text for details). (C) Autophagy. Misfolded proteins can be degraded by three modes of autophagy: macroautophagy, microautophagy or CMA. (D) The HSR. Molecular chaperones Hsp70, Hsp40 and Hsp90 can exist in a complex in the cytosol with their transcription factor HSF1. Upon binding misfolded proteins, Hsp70, Hsp40 and Hsp90 dissociate from HSF1, which can trimerise and activate via phosphorylation. This results in traffic to the nucleus leading to increased chaperone expression.
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