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Primary amines protect against retinal degeneration in mouse models of retinopathies

Nature Chemical Biology volume 8, pages 170–178 (2012)Cite this article

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Abstract

Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine–containing Food and Drug Administration (FDA)–approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal–induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration.

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Figure 1: Retinoid cycle and fate of atRAL in the retina.
Figure 2: Testing effects of amines on the development of acute light-induced retinal degeneration in Abca4−/− Rdh8−/− mice.
Figure 3: Effects of pre-administered amine drugs on light-induced acute retinal degeneration in 4-week-old Abca4−/− Rdh8−/− mice.
Figure 4: A20 stereoisomers protect against light-induced acute retinal degeneration in Abca4−/− Rdh8−/− mice.
Figure 5: Identification of retinal conjugates in retinas of Abca4−/− Rdh8−/− mice treated with A2 and A20.
Figure 6: Effects of treatment with amine drugs on age-related retinal degeneration in Abca4−/− Rdh8−/− mice.
Figure 7: Effects of preadministered amine drugs on light-induced retinal degeneration in BALB/c mice.

References

  1. Palczewski, K. G protein–coupled receptor rhodopsin. Annu. Rev. Biochem. 75, 743–767 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Palczewski, K. et al. Crystal structure of rhodopsin: a G protein–coupled receptor. Science 289, 739–745 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Travis, G.H., Golczak, M., Moise, A.R. & Palczewski, K. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. Annu. Rev. Pharmacol. Toxicol. 47, 469–512 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. von Lintig, J., Kiser, P.D., Golczak, M. & Palczewski, K. The biochemical and structural basis for trans-to-cis isomerization of retinoids in the chemistry of vision. Trends Biochem. Sci. 35, 400–410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rattner, A., Smallwood, P.M. & Nathans, J. Identification and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol. J. Biol. Chem. 275, 11034–11043 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Molday, R.S., Beharry, S., Ahn, J. & Zhong, M. Binding of N-retinylidene-PE to ABCA4 and a model for its transport across membranes. Adv. Exp. Med. Biol. 572, 465–470 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Maeda, A., Maeda, T., Golczak, M. & Palczewski, K. Retinopathy in mice induced by disrupted all-trans-retinal clearance. J. Biol. Chem. 283, 26684–26693 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Golczak, M., Kuksa, V., Maeda, T., Moise, A.R. & Palczewski, K. Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle. Proc. Natl. Acad. Sci. USA 102, 8162–8167 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Maeda, A. et al. Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice. Mol. Pharmacol. 70, 1220–1229 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Golczak, M. et al. Lecithin:retinol acyltransferase is responsible for amidation of retinylamine, a potent inhibitor of the retinoid cycle. J. Biol. Chem. 280, 42263–42273 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Maeda, A. et al. Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J. Biol. Chem. 284, 15173–15183 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Allikmets, R. et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat. Genet. 15, 236–246 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Cremers, F.P. et al. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Hum. Mol. Genet. 7, 355–362 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Martínez-Mir, A. et al. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat. Genet. 18, 11–12 (1998).

    Article  PubMed  Google Scholar 

  15. Zhang, Q. et al. Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3-p21.2 between D1S2896 and D1S457 but outside ABCA4. Hum. Genet. 118, 356–365 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Allikmets, R. Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am. J. Hum. Genet. 67, 487–491 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tsybovsky, Y., Molday, R.S. & Palczewski, K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. Adv. Exp. Med. Biol. 703, 105–125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Molday, R.S. & Zhang, K. Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog. Lipid. Res. 49, 476–492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhong, M., Molday, L.L. & Molday, R.S. Role of the C terminus of the photoreceptor ABCA4 transporter in protein folding, function, and retinal degenerative diseases. J. Biol. Chem. 284, 3640–3649 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Maeda, A. et al. Redundant and unique roles of retinol dehydrogenases in the mouse retina. Proc. Natl. Acad. Sci. USA 104, 19565–19570 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Sparrow, J.R., Wu, Y., Kim, C.Y. & Zhou, J. Phospholipid meets all-trans-retinal: the making of RPE bisretinoids. J. Lipid Res. 51, 247–261 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Parish, C.A., Hashimoto, M., Nakanishi, K., Dillon, J. & Sparrow, J. Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc. Natl. Acad. Sci. USA 95, 14609–14613 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Murdaugh, L.S. et al. Compositional studies of human RPE lipofuscin. J. Mass Spectrom. 45, 1139–1147 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Różanowska, M. & Sarna, T. Light-induced damage to the retina: role of rhodopsin chromophore revisited. Photochem. Photobiol. 81, 1305–1330 (2005).

    Article  PubMed  Google Scholar 

  25. Negre-Salvayre, A., Coatrieux, C., Ingueneau, C. & Salvayre, R. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br. J. Pharmacol. 153, 6–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Ellis, E.M. Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol. Ther. 115, 13–24 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Sun, H. & Nathans, J. ABCR, the ATP-binding cassette transporter responsible for Stargardt macular dystrophy, is an efficient target of all-trans-retinal–mediated photooxidative damage in vitro. Implications for retinal disease. J. Biol. Chem. 276, 11766–11774 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Mata, N.L., Weng, J. & Travis, G.H. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc. Natl. Acad. Sci. USA 97, 7154–7159 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Kim, Y.K. et al. Retinyl ester formation by lecithin: retinol acyltransferase is a key regulator of retinoid homeostasis in mouse embryogenesis. J. Biol. Chem. 283, 5611–5621 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Fishkin, N., Yefidoff, R., Gollipalli, D.R. & Rando, R.R. On the mechanism of isomerization of all-trans-retinol esters to 11-cis-retinol in retinal pigment epithelial cells: 11-fluoro-all-trans-retinol as substrate/inhibitor in the visual cycle. Bioorg. Med. Chem. 13, 5189–5194 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Yannuzzi, L.A. et al. Ophthalmic fundus imaging: today and beyond. Am. J. Ophthalmol. 137, 511–524 (2004).

    Article  PubMed  Google Scholar 

  32. Nickell, S., Park, P.S., Baumeister, W. & Palczewski, K. Three-dimensional architecture of murine rod outer segments determined by cryoelectron tomography. J. Cell Biol. 177, 917–925 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Holz, F.G. et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am. J. Ophthalmol. 143, 463–472 (2007).

    Article  PubMed  Google Scholar 

  34. Imanishi, Y., Batten, M.L., Piston, D.W., Baehr, W. & Palczewski, K. Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J. Cell Biol. 164, 373–383 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Taylor, C.P. et al. Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin. Epilepsy Res. 14, 11–15 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Field, M.J., Oles, R.J. & Singh, L. Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity. Br. J. Pharmacol. 132, 1–4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Golczak, M. et al. Metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the vertebrate retina. J. Biol. Chem. 283, 9543–9554 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dean, D.M., Nguitragool, W., Miri, A., McCabe, S.L. & Zimmerman, A.L. All-trans-retinal shuts down rod cyclic nucleotide-gated ion channels: a novel role for photoreceptor retinoids in the response to bright light? Proc. Natl. Acad. Sci. USA 99, 8372–8377 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Maeda, A. et al. Palmitoylation stabilizes unliganded rod opsin. Proc. Natl. Acad. Sci. USA 107, 8428–8433 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Maeda, A. et al. Retinol dehydrogenase (RDH12) protects photoreceptors from light-induced degeneration in mice. J. Biol. Chem. 281, 37697–37704 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kalia, J. & Raines, R.T. Hydrolytic stability of hydrazones and oximes. Angew. Chem. Int. Edn Engl. 47, 7523–7526 (2008).

    Article  CAS  Google Scholar 

  42. Weng, J. et al. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 98, 13–23 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Mata, N.L. et al. Delayed dark-adaptation and lipofuscin accumulation in abcr+/− mice: implications for involvement of ABCR in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 42, 1685–1690 (2001).

    CAS  PubMed  Google Scholar 

  44. Sparrow, J.R., Nakanishi, K. & Parish, C.A. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest. Ophthalmol. Vis. Sci. 41, 1981–1989 (2000).

    CAS  PubMed  Google Scholar 

  45. Vollmer-Snarr, H.R. et al. Amino-retinoid compounds in the human retinal pigment epithelium. Adv. Exp. Med. Biol. 572, 69–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Maeda, A. et al. Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo. J. Biol. Chem. 280, 18822–18832 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim, S.R. et al. Rpe65 Leu450Met variant is associated with reduced levels of the retinal pigment epithelium lipofuscin fluorophores A2E and iso-A2E. Proc. Natl. Acad. Sci. USA 101, 11668–11672 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Stecher, H. & Palczewski, K. Multienzyme analysis of visual cycle. Methods Enzymol. 316, 330–344 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stecher, H., Gelb, M.H., Saari, J.C. & Palczewski, K. Preferential release of 11-cis-retinol from retinal pigment epithelial cells in the presence of cellular retinaldehyde-binding protein. J. Biol. Chem. 274, 8577–8585 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Z. Dong for expert handling of mice, S. Roos for block preparation and plastic sectioning, J. Zhang for NMR analyses, and M. Matosky for retinoid analyses. We also thank L. Webster Jr, J. Saari, M.E. Maguire and members of the Palczewski laboratory for critical comments on the manuscript. This research was supported in part by grants EY009339, EY021126, EY019031, EY019880 and P30 EY11373 from the US National Institutes of Health; TECH 09–004 from the State of Ohio Department of Development; the Third Frontier Commission; Research to Prevent Blindness; Ohio Lion Eye Research Foundation; Foundation Fighting Blindness; and Fight for Sight.

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Author notes

  1. Akiko Maeda and Marcin Golczak: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA

    Akiko Maeda & Tadao Maeda

  2. Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA

    Akiko Maeda, Marcin Golczak, Yu Chen, Kiichiro Okano, Hideo Kohno, Satomi Shiose, Kaede Ishikawa, Tadao Maeda & Krzysztof Palczewski

  3. Polgenix Inc., Cleveland, Ohio, USA

    William Harte

  4. Visum Inc., Cleveland, Ohio, USA

    Grazyna Palczewska

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Contributions

A.M., M.G. and K.P. conceived and directed the project. A.M., M.G., T.M., Y.C., K.O., H.K., S.S. and K.I. designed and conducted experiments. G.P. and K.P. performed pharmacological analyses of the data. A.M., M.G. and K.P. prepared the manuscript. A.M., M.G., G.P., W.H. and T.M. analyzed the data and edited the manuscript.

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Correspondence to Krzysztof Palczewski.

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Competing interests

Case Western Reserve University and Visum Inc. may commercialize some of the technology described in this work. A.M., M.G. and T.M. are consultants for Visum Inc., and K.P. and W.H. are cofounders of Visum Inc.

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Maeda, A., Golczak, M., Chen, Y. et al. Primary amines protect against retinal degeneration in mouse models of retinopathies. Nat Chem Biol 8, 170–178 (2012). https://doi.org/10.1038/nchembio.759

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