Autophagy in light-induced retinal damage

Abstract

Vision is reliant upon converting photon signals to electrical information which is interpreted by the brain and therefore allowing us to receive information about our surroundings. However, when exposed to excessive light, photoreceptors and other types of cells in the retina can undergo light-induced cell death, termed light-induced retinal damage. In this review, we summarize our current knowledge regarding molecular events in the retina after excessive light exposure and mechanisms of light-induced retinal damage. We also introduce works which investigate potential roles of autophagy, an essential cellular mechanism required for maintaining homeostasis under stress conditions, in the illuminated retina and animal models of light-induced retinal damage.

Keywords: ATG7; All-trans-retinal; Beclin1; Light-induced retinal damage; Park2; Visual cycle.

Figure 1. Vitamin A metabolism in the eye

Vitamin A (all-trans-ROL, retinol) is supplied from blood circulation by the concerted action of serum retinol-binding protein (RBP), stimulated by retinoic acid 6 (STRA6), cellular retinol-binding protein type 1 (CRBP1) and lecithin:retinol acyl transferase (LRAT). Vitamin A is stored as all-trans-retinyl ester (all-trans-RE) in the retinosomes of RPE cells. RPE65 isomerizes all-trans-RE to 11-cis-ROL and then 11-cis-retinol dehydrogenases (RDHs), such as RDH5 and RDH11, oxidize 11-cis-ROL to 11-cis-RAL. 11-cis-RAL binds to retinoid binding proteins, including cellular retinaldehyde-binding protein (CRALBP) and inter-photoreceptor retinoid-binding protein (IRBP), and is then transported to photoreceptors to regenerate light-sensitive rhodopsin. When light hits the light-sensitive form of rhodopsin, 11-cis-RAL is photo-isomerized to all-trans-RAL. This conformational change initiates rhodopsin activation. All-trans-RAL is largely released from rhodopsin into the cytosolic lumen of rod photoreceptor cell outer segments, but a fraction remains in the intra-discal lumen. ATP-binding cassette transporter (ABCA4) removes the remaining aldehyde from the intra-discal lumen. Collectively all-trans RAL is reduced by all-trans-retinol dehydrogenases (RDHs, including RDH8 and RDH12) to all-trans-ROL. All-trans-ROL is transported back to RPE cells by binding with IRBP and CRBP1.

Figure 2. Autophagic vesicles in the rod photoreceptor cell and the RPE cell

The distribution of dots demonstrates the localization of autophagic vesicles in the rod photoreceptor cell and the RPE cell (Remé, 1977). Reme CE et. al. examined localization of autophagic vacuoles in photoreceptors of normal animals from five different species (cat, rat, frog, goldfish, ground squirrel) by electron microscopic analysis. In the rod photoreceptor cells, autophagic vesicles are found more often in the myoid (M), the ellipsoid (E) and the perinuclear area (PN). Autophagic vesicles are less frequently observed in the connecting fiber between the nucleus and synaptic body. Autophagic events have not been documented in the outer segment. Autophagic vesicles are found widely dispersed in the cytoplasm of RPE cells.

Figure 3. Normal retinal morphology in Beclin1^+/− mice raised under room lighting conditions

Beclin1^+/− and littermate wild-type control Beclin1^+/+ mice were raised under room lighting conditions (12 h light at 10 Lux /12 h dark), and retinal histology was evaluated at the age of 2 months. Beclin1^+/− retinas show normal morphology similar to the retinas of Beclin1^+/+ mice. Rod photoreceptors, cone photoreceptors and nuclei were stained by anti-rhodopsin antibody (red), peanut agglutinin (PNA, green) and DAPI (blue), respectively. RPE, retinal pigmented epithelium; OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bars indicate 30 μm.

Figure 4. Increased susceptibility to light-induced retinal damage as a result of Beclin1 deficiency

Beclin1^+/− mice and Beclin1^+/+ littermate controls at 2 months of age were exposed to white light at 5,000 Lux for 2 hours. Plastic sections were prepared from light-exposed Beclin1^+/− mice and Beclin1^+/+ littermate controls 7 days after the illumination. Severely disrupted photoreceptor structure was marked by degenerated photoreceptor outer segment and inner segment and significantly reduced thickness of ONL in Beclin1^+/− eyes as compared to the intact photoreceptor structure displayed by Beclin1^+/+ eyes. RPE, retinal pigmented epithelium; OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bars indicate 30 μm.