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Review
. 2012 Nov-Dec;88(6):1309-19.
doi: 10.1111/j.1751-1097.2012.01143.x. Epub 2012 Apr 24.

Retinal photodamage mediated by all-trans-retinal

Tadao Maeda  1 , Marcin Golczak, Akiko Maeda
Affiliations
Review

Retinal photodamage mediated by all-trans-retinal

Tadao Maeda et al. Photochem Photobiol. 2012 Nov-Dec.

Abstract

Accumulation of all-trans-retinal (all-trans-RAL), reactive vitamin A aldehyde, is one of the key factors in initiating retinal photodamage. This photodamage is characterized by progressive retinal cell death evoked by light exposure in both an acute and chronic fashion. Photoactivated rhodopsin releases all-trans-RAL, which is subsequently transported by ATP-binding cassette transporter 4 and reduced to all-trans-retinol by all-trans-retinol dehydrogenases located in photoreceptor cells. Any interruptions in the clearing of all-trans-RAL in the photoreceptors can cause an accumulation of this reactive aldehyde and its toxic condensation products. This accumulation may result in the manifestation of retinal dystrophy including human retinal degenerative diseases such as Stargardt's disease and age-related macular degeneration. Herein, we discuss the mechanisms of all-trans-RAL clearance in photoreceptor cells by sequential enzymatic reactions, the visual (retinoid) cycle, and potential molecular pathways of retinal photodamage. We also review recent imaging technologies to monitor retinal health status as well as novel therapeutic strategies preventing all-trans-RAL-associated retinal photodamage.

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Figures

Figure 1
Figure 1. Process of all-trans-RAL clearance and accumulation of condensation byproducts
All-trans-RAL is a one of the major vitamin A metabolites in the retina. In physiological conditions, all-trans-RAL is regenerated to the visual chromophore, 11-cis-retinal. The absorption of a photon (hν) by a visual pigment (rhodopsin) causes isomerization of 11-cis-RAL to all-trans-RAL, resulting in rhodopsin activation (rhodopsin*). The majority of all-trans-RAL is released from photoactivated rhodopsin into the cytosolic space of photoreceptor outer segments, and a fraction of all-trans-RAL is released to the intradiscal space. Clearance of all-trans-RAL is achieved via two processes. First all-trans-RAL is transported out from the intradiscal space into the cytosol by a photoreceptor specific ATP-binding transporter 4 (ABCA4) and reduced to all-trans-ROL by all-trans-RAL dehydrogenases (all-trans-RDHs; RDH8 and RDH12). Secondly all-trans-ROL diffuses into the RPE where it is esterified, isomerized and converted to 11-cis-RAL by sequential enzymatic reactions involving lecithin: retinol acyltransferase (LRAT), retinal pigment epithelium-specific 65 kDa protein (RPE65) and 11-cis-RDHs including RDH5, and then diffuses back into the photoreceptor where it regenerates rhodopsin. This 11-cis-RAL recycling system is termed the visual (retinoid) cycle. When clearing of all-trans-RAL is delayed, excess of all-trans-RAL accumulates in the form of its condensation products with PE in photoreceptor outer segments. N-retinylidene-phosphatidylethanolamine (N-ret-PE) and free all-trans-RAL are conjugated to form a phosphatidylpyridinium-bisretinoid (A2PE), a precursor of A2E, which escapes from ABCA4 transporting and accumulates in the intradiscal space. Accumulated A2PE is phagocytized by the RPE along with photoreceptor outer segments, and is converted to A2E by lysosomal digestion in the RPE.
Figure 2
Figure 2. Clearance of all-trans-RAL and accumulation of condensation byproduct (A2E) in RDHs and ABCA4 deficient mice
(A) Clearance of all-trans-RAL was compared among 6-week old mice. After flash light exposure, eye retinoids were extracted and quantified by normal phase HPLC to evaluate effects of Rdh8, Rdh12, Abca4 genes and double or triple combinations of these genes on the clearance of all-trans-RAL from the retina. There was no difference in all-trans-RAL levels under fully dark-adapted condition between all these strains. Rdh8−/− mice displayed the most significant delay of all-trans-RAL clearance compared to other mice with only a single gene deletion. The double and triple genes deletions elongated all-trans-RAL clearance. (B) Amounts of A2E were quantified by reverse phase HPLC. Age-dependent accumulation of A2E was observed in mutant mice, and the accumulation levels were correlated with the delay of all-trans-RAL clearance. Bars indicate SD.
Figure 3
Figure 3. Chronic and acute retinal photodamage in Rdh8−/−Abca4−/−mice
Rdh8−/−Abca4−/−mice exhibit severe retinal photodamage due to excess accumulation of all-trans-RAL. Epon-embedded retina cross-section images (A) and in vivo high-definition spectral-domain optical coherent tomography images (B) were obtained from Rdh8−/−Abca4−/−mice with chronic and acute photodamage. The disruption of the outer nuclear layer (ONL) with a decreasing number of photoreceptor cells was manifested compared to age-matched Rdh8+/+Abca4+/+ mouse retina (A left and middle panels) under regular cyclic light at 4 months of age. In vivo retinal image was obtained from these mice by spectral domain optical coherent tomography (SD-OCT). In Rdh8−/−Abca4−/−mice, disruption of ONL was demonstrated in the inferior retina (B upper panel) although Rdh8+/+Abca4+/+ retina maintained normal structure (B lower panel). Acute retinal photodamage was induced in Rdh8−/−Abca4−/−mice (6 weeks old) by intense light exposure (10,000 lux for 30 min) and retinal cross section images were obtained at 14 days after light exposure. Most of photoreceptors were disappeared and only debris of dead photoreceptor cells were accumulated in the subretinal space (A right panel). SD-OCT image showed only residual ONL layer and debris accumulation as well (white arrows in B middle panel). INL, inner nuclear layer; IS, inner segment; ONL, outer nuclear layer; OS, outer segment. Scale bar in A indicates 40 μm.
Figure 4
Figure 4. In vivo imaging of age-dependent accumulation of all-trans-RAL condensation products in mouse eye
In vivo fundus images by scanning laser ophthalmoscopy (SLO) in autofluorescent mode (AF mode) (A) and ex vivo images of the RPE by two-photon microscopy (TPM) (B) were obtained from Rdh8−/−Abca4−/−mice. (A) Age-dependent increase of AF levels was observed across the entire fundus in Rdh8−/−Abca4−/−mouse eye but only low level AF was observed in age-matched Rdh8+/+Abca4+/+mouse. Infiltration of inflammatory cells which engulfed photoreceptor debris was observed as white dots (yellow arrows) sporadically in the fundus ofRdh8−/−Abca4−/−mice. These SLO images were obtained at AF mode with 3 second exposure to 488 nm excitation. (B) Higher intensity of autofluorescence which indicates higher level accumulation of all-trans-RAL condensation products was specifically detected by TPM using 850 nm excitation in the cytoplasmic space of the RPE in Rdh8−/−Abca4−/−mouse eye at 6 months of age (B left panel) when compared to those of age-matched Rdh8+/+Abca4+/+ mice (B right panel). Scale bar in B indicates 30 μm.
Figure 5
Figure 5. Pharmacological innovation to protect photodamage mediated by all-trans-RAL
Accumulation of all-trans-RAL is prevented by two pharmacological actions of retinylamine (Ret-NH2). First, free all-trans-RAL is neutralized by Schiff base formation between all-trans-RAL and Ret-NH2 (A). This chemical reaction can be monitored in a color change in the reaction-mixture. Second, free all-trans-RAL generation can be decreased by the inhibitory action of Ret-NH2 in the visual cycle. Specific-binding of Ret-NH2 to RPE65 can prevent an isomerization reaction and slow down regeneration of 11-cis-RAL, which can consequently decrease free all-trans-RAL during light exposure. These two pharmacological actions can protect Rdh8−/−Abca4−/−retina from photodamage (B). Representative in vivo retinal images by high-definition SD-OCT clearly reveal that Rdh8−/−Abca4−/− mice treated with Ret-NH2 can maintain normal morphology of the retina whereas outer nuclear layer (ONL) are severely degenerated in vehicle treated mice. INL, inner nuclear layer; ONL, outer nuclear layer; OS, outer segment.
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