During the previous grant period we showed that 11-cis retinal, the light-detecting chromophore of the visual pigment, is the primary source of the toxic deposits that accumulate in the Retinal Pigment Epithelium (RPE) as lipofuscin in the human retina. We also showed that central RPE, the area underlying the macula, contains low levels of these toxic deposits. Defects of retinoid processing have long been linked to diseases of the retina, and the pivotal role played by 11-cis retinal as a mediator of acute and long-term damage suggests specific points in the processing pathway as potential therapeutic targets. In the previous funding period we focused exclusively on rods, which comprise more than 90% of the photoreceptor cells of the human retina. Here, we shift our attention to cone photoreceptors, which are the ones supporting vision for most of our daily activities, and are concentrated in the macula, the part of the retina responsible for high acuity vision. Both the 11-cis and all-trans isomers of retinal are highly reactive aldehydes and photosensitizers, and their reactions with photoreceptor components give rise to the toxic deposits that accumulate in the RPE in the form of lipofuscin. In contrast to rods, which use 11-cis retinal, cones use 11-cis retinol as the source for their visual pigment chromophore. 11-Cis retinol is oxidized to 11-cis retinal within the cell and is far less toxic than either 11-cis or all-trans retinal. We will determine and compare the damage mediated by all-trans retinal, 11- cis retinal and 11-cis retinol in single living cone photoreceptors isolated from monkey and human donor eyes. We will use fluorescence imaging of single photoreceptors to measure oxidative damage and the formation of lipofuscin fluorophore precursors.
The aims of the research are:
Specific Aim #1 : Determine the damage-causing potential of all-trans retinal in cone outer segments.
Specific Aim #2 : Determine the damage-causing potential of 11-cis retinal in cone outer segments.
Specific Aim #3 : Determine the damage-causing potential of 11-cis retinol in cone outer segments. Results from these studies will provide new insights into the basic pathogenic mechanisms operating in the macula and underlying vision loss in diseases like Age-related Macular Degeneration (AMD). They will investigate the specialized mechanisms employed by cone photoreceptors to protect the macula from retinaldehyde toxicity. They will allow the evaluation of the potential toxicity of therapies for visual pigment chromophore deficiencies that depend on boosting the chromophore supply; they will also provide a measure for the expected effectiveness of the opposite type of therapies, which aim to limit lipofuscin formation by slowing down the generation of 11-cis retinal.
Rod and cone vertebrate photoreceptor cells use a form of vitamin A to detect light; processing of this form within photoreceptors gives rise to toxic deposits that have been implicated in diseases such as Age-Related Macular Degeneration and Stargardt. Cone photoreceptors support daytime vision and are concentrated in the macula, the part of the retina responsible for high acuity vision. This project will use living cone photoreceptors isolated from monkey and human donor eyes to characterize specialized mechanisms employed by cone cells to prevent the formation of toxic deposits and protect the macula.
| Chen, Chunhe; Adler 4th, Leopold; Goletz, Patrice et al. (2017) Interphotoreceptor retinoid-binding protein removes all-trans-retinol and retinal from rod outer segments, preventing lipofuscin precursor formation. J Biol Chem 292:19356-19365 |
| Sheridan, Colleen; Boyer, Nicholas P; Crouch, Rosalie K et al. (2017) RPE65 and the Accumulation of Retinyl Esters in Mouse Retinal Pigment Epithelium. Photochem Photobiol 93:844-848 |
| Adler 4th, Leopold; Chen, Chunhe; Koutalos, Yiannis (2017) All-trans retinal levels and formation of lipofuscin precursors after bleaching in rod photoreceptors from wild type and Abca4-/- mice. Exp Eye Res 155:121-127 |
| Frederiksen, Rikard; Nymark, Soile; Kolesnikov, Alexander V et al. (2016) Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods. J Gen Physiol 148:1-11 |
| Adler 4th, Leopold; Boyer, Nicholas P; Chen, Chunhe et al. (2015) The 11-cis Retinal Origins of Lipofuscin in the Retina. Prog Mol Biol Transl Sci 134:e1-12 |
| Adler 4th, Leopold; Boyer, Nicholas P; Anderson, David M et al. (2015) Determination of N-retinylidene-N-retinylethanolamine (A2E) levels in central and peripheral areas of human retinal pigment epithelium. Photochem Photobiol Sci 14:1983-90 |
| Pallitto, Patrick; Ablonczy, Zsolt; Jones, E Ellen et al. (2015) A2E and lipofuscin distributions in macaque retinal pigment epithelium are similar to human. Photochem Photobiol Sci 14:1888-95 |
| Crouch, Rosalie K; Koutalos, Yiannis; Kono, Masahiro et al. (2015) A2E and Lipofuscin. Prog Mol Biol Transl Sci 134:449-63 |
| Adler 4th, Leopold; Chen, Chunhe; Koutalos, Yiannis (2014) Mitochondria contribute to NADPH generation in mouse rod photoreceptors. J Biol Chem 289:1519-28 |
| Ablonczy, Zsolt; Smith, Noah; Anderson, David M et al. (2014) The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry. Proteomics 14:936-44 |
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