Multiple and Additive Functions of ALDH3A1 and ALDH1A1

Abstract

ALDH3A1 (aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower (catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation (lens opacification). The Aldh1a1/Aldh3a1- and Aldh3a1-null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life (6–9 months of age). One- to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic (light filtering) and enzymatic (detoxification) functions. ALDH3A1 (aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower (catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation (lens opacification). The Aldh1a1/Aldh3a1- and Aldh3a1-null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life (6–9 months of age). One- to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic (light filtering) and enzymatic (detoxification) functions. The cornea serves as a physical and biochemical protective barrier between the external milieu and internal ocular tissues. The anterior segment of the eye absorbs the major fraction of the UV light entering the eye and acts as a filter, protecting the lens and retina from UV-induced damage (1Ringvold A. Acta Ophthalmol. Scand. 1998; 76: 149-153Crossref PubMed Scopus (95) Google Scholar). UV radiation-induced pathologic changes in the eye are associated with the generation of reactive oxygen species (ROS) 2The abbreviations used are:ROSreactive oxygen speciesLPOlipid peroxidationSODsuperoxide dismutase4-HNE4-hydroxy-2-nonenalMDAmalondialdehydeGCSγ-glutamylcysteine synthaseWTwild type. that cause lipid peroxidation (LPO), protein modification and denaturation, and DNA damage (2Spector A. FASEB J. 1995; 9: 1173-1182Crossref PubMed Scopus (793) Google Scholar, 3Spector A. J. Ocul. Pharmacol. Ther. 2000; 16: 193-201Crossref PubMed Scopus (210) Google Scholar). These effects may cause reduction of corneal epithelial cell viability and cell death by apoptotic pathways (4Shinohara T. Singh D.P. Chylack Jr., L.T. J. Ocul. Pharmacol. Ther. 2000; 16: 181-191Crossref PubMed Scopus (46) Google Scholar) as well as protein denaturation with the loss of tertiary structural relationships in the lens fibers, essential for transparency (3Spector A. J. Ocul. Pharmacol. Ther. 2000; 16: 193-201Crossref PubMed Scopus (210) Google Scholar). Exposure to solar radiation, particularly within the UV wavelengths, is a risk factor for the development of age-related cataracts and macular degeneration in the retina as well as some corneal diseases (5Cruickshanks K.J. Klein B.E. Klein R. Am. J. Public Health. 1992; 82: 1658-1662Crossref PubMed Scopus (219) Google Scholar, 6Tomany S.C. Cruickshanks K.J. Klein R. Klein B.E. Knudtson M.D. Arch. Ophthalmol. 2004; 122: 750-757Crossref PubMed Scopus (233) Google Scholar). reactive oxygen species lipid peroxidation superoxide dismutase 4-hydroxy-2-nonenal malondialdehyde γ-glutamylcysteine synthase wild type. The cornea expresses several proteins that minimize the damaging effects of UV radiation to the more internal structures. The corneas of all mammals are rich in antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, and catalase, that protect other proteins against the oxidative effects of ROS generated by UV light (7Buddi R. Lin B. Atilano S.R. Zorapapel N.C. Kenney M.C. Brown D.J. J. Histochem. Cytochem. 2002; 50: 341-351Crossref PubMed Scopus (284) Google Scholar). Nuclear ferritin, detected in chicken corneal epithelium, protects against UV-induced DNA oxidative damage (8Cai C.X. Birk D.E. Linsenmayer T.F. Mol. Biol. Cell. 1998; 9: 1037-1051Crossref PubMed Scopus (109) Google Scholar). The corneal epithelium of most mammalian species expresses low molecular weight scavengers of ROS, such as glutathione, α-tocopherol, ascorbate, and NADPH (9van Haaften R.I. Haenen G.R. Evelo C.T. Bast A. Drug Metab. Rev. 2003; 35: 215-253Crossref PubMed Scopus (56) Google Scholar, 10Ringvold A. Anderssen E. Kjonniksen I. Invest. Ophthalmol. Vis. Sci. 1998; 39: 2774-2777PubMed Google Scholar). NADPH is essential for the regeneration of GSH from its oxidized form (GSSG) through the glutathione reductase/peroxidase system, serving as an indirect antioxidant by maintaining the reducing power of GSH (11Atherton S.J. Lambert C. Schultz J. Williams N. Zigman S. Photochem. Photobiol. 1999; 70: 823-828Crossref PubMed Scopus (23) Google Scholar). NADPH may also function as a direct antioxidant by reducing glutathiyl and tyrosyl radicals generated during oxidative stress (12Kirsch M. De G.H. FASEB J. 2001; 15: 1569-1574Crossref PubMed Scopus (250) Google Scholar). Additionally, this molecule directly absorbs UV light (11Atherton S.J. Lambert C. Schultz J. Williams N. Zigman S. Photochem. Photobiol. 1999; 70: 823-828Crossref PubMed Scopus (23) Google Scholar) and protects biomolecules through direct binding. For example, bound NADPH is known to offset H2O2-induced inactivation of catalase (13Kirkman H.N. Rolfo M. Ferraris A.M. Gaetani G.F. J. Biol. Chem. 1999; 274: 13908-13914Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar). Corneal crystallins, which are proteins expressed in high levels similar to lens crystallins, are thought to also play a protective role against UV-induced damage (14Piatigorsky J. Prog. Retin. Eye Res. 1998; 17: 145-174Crossref PubMed Scopus (127) Google Scholar). The NADP+-dependent isocitrate dehydrogenase, a bovine corneal crystallin, plays a protective role against UV-induced oxidative injury by preventing LPO, protein oxidation, oxidative DNA damage, and intracellular peroxide generation (15Lee S.M. Koh H.J. Park D.C. Song B.J. Huh T.L. Park J.W. Free Radic. Biol. Med. 2002; 32: 1185-1196Crossref PubMed Scopus (342) Google Scholar). Albumin, the most prevalent protein in the corneal stroma, may serve as an antioxidant scavenger of hydrogen peroxide and protects the cornea against oxidative damage (16Nees D.W. Fariss R.N. Piatigorsky J. Invest Ophthalmol. Vis. Sci. 2003; 44: 3339-3345Crossref PubMed Scopus (21) Google Scholar). Two aldehyde dehydrogenases, ALDH3A1 and ALDH1A1, are of interest (17King G. Holmes R. J. Exp. Zool. 1998; 282: 12-17Crossref PubMed Google Scholar, 18Piatigorsky J. J. Ocul. Pharmacol. Ther. 2000; 16: 173-180Crossref PubMed Scopus (54) Google Scholar). ALDH3A1 represents 5–50% of the corneal water-soluble proteins in mammalian species (19Piatigorsky J. Ann. N. Y. Acad. Sci. 1998; 842: 7-15Crossref PubMed Scopus (121) Google Scholar), although it appears to be absent from the lens, whereas ALDH1A1 is found mainly in the lens and to a lesser extent (<5%) in the cornea (17King G. Holmes R. J. Exp. Zool. 1998; 282: 12-17Crossref PubMed Google Scholar). Early studies have suggested a protective role of ALDH3A1 against UV-induced damage in the cornea. SWR/J mice are susceptible to UV-induced cornea clouding (20Downes J.E. Swann P.G. Holmes R.S. Cornea. 1994; 13: 67-72Crossref PubMed Scopus (43) Google Scholar), apparently from a of ALDH3A1 to several in the T. J. 1999; 9: Google Scholar, A. Chem. Biol. 2001; 181-191Crossref PubMed Scopus Google Scholar). the is well by which ALDH3A1 and ALDH1A1 protect the corneal epithelium from UV-induced oxidative damage is the of reactive of LPO, such as 4-hydroxy-2-nonenal and malondialdehyde ALDH3A1 A. T. R. Brown J. 2003; PubMed Scopus Google Scholar), whereas ALDH1A1 and R. T. A. DNA Cell. Biol. 2003; PubMed Scopus Google Scholar). the of ALDH1A1 may more of the to ALDH3A1 and may a of which is a of ALDH3A1 A. T. R. Brown J. 2003; PubMed Scopus Google Scholar). of ocular ALDH3A1 direct of UV radiation, activity, and of ROS via the of the and in T. Piatigorsky J. N. Exp. Eye Res. PubMed Scopus Google Scholar). that the and Aldh3a1(-/-) single as well as the Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice develop cataracts (lens the of these proteins and in preventing ocular These studies have for cataract formation in and Aldh1a1(-/-)/Aldh3a1(-/-) mice and wild type were of Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out A. S. G. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar, D.W. Jr., Piatigorsky J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice were generated by of Aldh1a1(-/-) and Aldh3a1(-/-) mice are of and the of all knock-out used in this were in a a and with and to of and at were used for was in with and of the of and was to the of of and transparency of the cornea and lens in the wild Aldh1a1(-/-) and Aldh3a1(-/-) single and double knock-out mice of and months of was was induced by a of of and in animals. eye and were by a To the was to the of the mice To the extent of lens opacification, a cataract from to 1 and was The was during the to minimize of light and were for during the The and posterior regions of the lens were of light from cornea and lens were by a of through the of the eye with cornea to an of that all the corneal A. J. T. J. T. P.G. Invest. Ophthalmol. Vis. Sci. 2004; PubMed Scopus Google Scholar). changes in protein to the of ALDH1A1 and ALDH3A1 corneal and of dehydrogenase and reductase, which are major enzymes, as well as antioxidant and glutathione and corneal were evaluated in all by and of and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice were by by and were from by posterior to the and corneas from at were in 1 and were for a and for for a of were at for at and were for by were the and of protein was and to a For of protein from lens and cornea were to and to A. C. Y. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). The A. S. G. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar), and A. T. R. Brown J. 2003; PubMed Scopus Google Scholar), to from M. of catalase glutathione Piatigorsky J. Mol. Cell. Biol. 2002; PubMed Scopus (54) Google Scholar), dehydrogenase G. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), and γ-glutamylcysteine synthase from T. of and were from proteins were detected by ALDH3A1 was and and 1 as A. C. Y. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). ALDH3A1 was to protein by the of GSH from wild and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice months of were and the and corneas were and for The were an in and and in the at for in the of the development of the The was by the of the were at for at and the was and for GSH a high with a as with B.J. A.M. E. 2004; PubMed Scopus Google Scholar). of and and were from wild type and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out and the and were as C. Invest. Ophthalmol. Vis. Sci. 2003; 44: PubMed Scopus Google Scholar). of from were for of the the and were with to the to The protein were to and for the of The were for of and by against and proteins from of proteins were detected by from wild and Aldh3a1(-/-) single and double knock-out mice were to in and for as M. C. B. Free Radic. Biol. Med. 2002; 32: PubMed Scopus Google Scholar). The was a were at for 1 in a a The and the were and were with the to to UVB to three-month-old wild and Aldh3a1(-/-) single and double knock-out mice were exposed to UVB light for and and lens was evaluated and UV by were by of and and were directly the UV with the its that eye the at a were exposed to of The UV with a of was in an The from the to the eye was The of the at this was to be a to a from the to the of the was In the of the lens was are expressed as were of between were of test with of the of mice with lens between single double knock-out mice and mice was of was was Aldh1a1(-/-)/Aldh3a1(-/-) DNA of the mice the of the double knock-out and wild type The was by A. S. G. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar), whereas the was by D.W. Jr., Piatigorsky J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar) The mice were in the with that Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice are and The of ALDH1A1 and ALDH3A1 proteins in the double knock-out mice in lens and cornea was and ALDH1A1 protein was from the lens of Aldh1a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) ALDH3A1 was from the cornea of the Aldh1a1(-/-)/Aldh3a1(-/-) mice but from the cornea of Aldh1a1(-/-) mice is also that other proteins are present in the of in cornea lens of the Aldh1a1(-/-)/Aldh3a1(-/-) mice as a that the was generated ALDH1A1 was detected in the lens and cornea of the wild type and Aldh3a1(-/-) mice but in Aldh1a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) ALDH3A1 was detected in the cornea but in the lens of wild type and in Aldh1a1(-/-) ALDH3A1 was absent from the cornea and lens of Aldh3a1(-/-) and double knock-out of enzymatic were detected in the cornea lens of Aldh1a1(-/-)/Aldh3a1(-/-) mice and and as and which that by other in the Aldh1a1(-/-)/Aldh3a1(-/-) in cornea and lens in wild type and double knock-out mice are expressed as of protein as from in and were and and as and enzymatic detected are expressed as of protein as from in and were and and as and enzymatic detected in a of mice and months were evaluated for cataract by the cataract a from to 1 and The of wild type mice were in most although a and of cataract was detected in the and and The Aldh1a1(-/-) mice a detected in of the mice Cataract was undetectable in Aldh1a1(-/-) whereas anterior subcapsular cataract as compared with the wild type and Cataract was in Aldh3a1(-/-) mice as as 1 month of as compared with wild type this was in mice as compared with Aldh3a1(-/-) and wild type mice and of the and Aldh3a1-null to lens in the anterior subcapsular and and The Aldh1a1(-/-)/Aldh3a1(-/-) mice exhibited the of cataracts at all with the anterior subcapsular as compared with wild type mice and and The cataract was in in mice in the double knock-out as compared with wild type mice in the anterior of the lens was in the double knock-out Aldh1a1(-/-)/Aldh3a1(-/-) as compared with single knock-out Aldh1a1(-/-) Aldh3a1(-/-) and wild type mice Cataract was in the anterior subcapsular and posterior regions in a double knock-out mouse of more months of subcapsular opacities and opacities were in the posterior cortex and in with the which was and wild type mice although a cataracts with in wild and single and double knock-out mice by in Cataract was in wild and single and double knock-out mice and months of with of mice with cataracts and single and double knock-out mice wild type mice was single and double knock-out for the and double knock-out mice were from the mice was between the double knock-out and the mice For the the mice were from the mice other between knock-out mice were of mice with cataracts and single and double knock-out mice wild type mice was single and double knock-out for the and double knock-out mice were from the mice was between the double knock-out and the mice For the the mice were from the mice other between knock-out mice were in a and in were in the corneal and of dehydrogenase and reductase, major enzymes, as well as antioxidant glutathione and corneal between wild type and and was and with to of GSH in the and of and of GSH was in animals. with wild type was a and GSH in the lens of and double knock-out In a and GSH in the cornea of and double knock-out compared with the wild type animals. was an in GSH for the lens and which was in the double knock-out mice In increased levels of GSH were also with an in the of which is a of a and light was undetectable in lens to the mice are mice are with low levels of GSH Y. D.W. Free Radic. Biol. Med. 2004; PubMed Scopus Google Scholar, Y. Y. D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google of GSH in and corneal from wild and double knock-out mice at months of The are expressed as of were of was an in GSH for the lens and cornea this was in the double knock-out in the the test the with the wild type in the the test the with the wild type in a in lens from and denaturation of the lens proteasomal in mice by the of the in the fraction of of all of mice at and months of age). in was in the with the double knock-out mice the of as compared with wild type and and in the of proteins as well as and proteins were detected in the lens from wild type and double knock-out These the in oxidized proteins as well as the of and proteins in the of in double knock-out mice as compared with the wild type animals. Corneal and Cataract exhibited anterior subcapsular lens and corneal at UVB which were more in Aldh3a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice and and Exposure to a high UV to the development of corneal in all mice that was more pronounced in Aldh3a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice compared with Aldh1a1(-/-) and wild type and In from the were used to the of the UVB of the in all in Aldh3a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice accelerated cataract formation and the in mice with single and double knock-out of the ALDH1A1 and the of these in the of cataract of ALDH3A1 and ALDH1A1 in these mice increased lens opacification, decreased proteasomal activity, and increased oxidative damage of increased levels of as well as and proteins in the lens of the double knock-out mice as compared with wild type animals. UV radiation to the of ROS in the lens and the risk of cataract formation in ROS LPO, which such as and that are and to of in protein denaturation, and Res. 2000; 32: PubMed Scopus Google Scholar). of protein as well as and a of protein oxidative damage T. T. K.J. FASEB J. PubMed Scopus Google Scholar, Ann. N. Y. Acad. Sci. 2000; PubMed Scopus Google Scholar). levels of are associated with the of in corneal (7Buddi R. Lin B. Atilano S.R. Zorapapel N.C. Kenney M.C. Brown D.J. J. Histochem. Cytochem. 2002; 50: 341-351Crossref PubMed Scopus (284) Google Scholar), with cataracts Mol. Med. PubMed Scopus (43) Google Scholar, A. B. N. A. R. 2004; PubMed Scopus Google Scholar), and with macular degeneration C. J. M.D. 1999; 13: PubMed Scopus Google Scholar). the of the by in lens opacities were in all found cataracts in most Aldh3a1(-/-) single knock-out mice as as 1 month of whereas the wild type mice In Aldh1a1(-/-) single knock-out lens was in the Aldh3a1(-/-) single knock-out and Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out mice and was also to later in The double knock-out mice lens in the anterior subcapsular at all compared with single and and wild type For this the double knock-out cataract in the of mice with cataracts was in the double knock-out mice and was as as 1 month of this increased as compared with wild type animals. months of the double knock-out mice anterior and posterior subcapsular cataracts with punctate and opacities with a these that ALDH1A1 and ALDH3A1 in protecting against cataract mice have of other antioxidant the protective of ALDH1A1 and ALDH3A1 against UV-induced cataract formation be a direct the of ALDH3A1 from the corneal epithelium and in the knock-out mice A. 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The role of ALDH1A1 as a light is this is expressed in the cornea at levels with the of these in increased oxidative damage and proteins in the lens, and this is the for cataract In this found that all of the increased levels of The double knock-out mice have the of GSH as compared with in lens and cornea a to oxidative stress in these animals. to oxidative stress changes in GSH which is through enzymatic reduction of its (GSSG) through GSH is a major of the in lens and cornea E. Eye Res. PubMed Scopus Google Scholar, Prog. Eye Res. 2003; PubMed Scopus Google Scholar). GSH is in the cell by the of and glutathione synthase in a of which have as the A. Rev. PubMed Scopus Google Scholar). appears to be to by of is a a and (light is for the activity, whereas the the of the for and its to by GSH Y. D.W. Free Radic. Biol. Med. 2004; PubMed Scopus Google Scholar). are expressed in ocular E. Eye Res. PubMed Scopus Google Scholar), and are by Free Radic. Biol. Med. 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The in in the double knock-out mice is to increased levels of protein The age-related of oxidized proteins is in by loss of the of the in the double knock-out and the proteins are susceptible to The of ALDH3A1 and ALDH1A1 proteins in the double knock-out mice in the of oxidized proteins as compared with wild type These findings that ALDH3A1 and ALDH1A1 protect the against oxidative stress and the protective of in ocular tissues. The and proteins in the double knock-out The lens protein from the double knock-out mice levels of protein as well as proteins to and compared with wild type have also increased protein in lens and cornea of Aldh3a1(-/-) knock-out mice M. D.W. Piatigorsky J. A. Invest. Ophthalmol. Vis. Sci. 2004; Scholar). Cataract formation in the double knock-out mice with the increased levels of and The oxidative effects of increased and and in with decreased are to be the of the cataracts in the animals. The in and the formation of as well as and proteins to the protein and cataract formation in the double knock-out the formation of protein lens by of the effects of UV-induced oxidative stress are In conclusion, that ALDH1A1 in the lens and cornea with ALDH3A1 in the cornea protect the mouse lens against through and of lipid peroxide and of oxygen radicals in the lens by ALDH1A1 protein and was that the of ALDH3A1 to lens opacification, that this is undetectable in wild type mouse by Aldh3a1-null mice corneal D.W. Jr., Piatigorsky J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). nonenzymatic role for corneal ALDH3A1 suggested the high of water-soluble which is is for a the for the in mice is that ALDH3A1 absorbs UV light in the wild type the of UV radiation that the lens. The that ALDH3A1 acts as a corneal for UV light was by M. T. Holmes R.S. Exp. Eye Res. PubMed Scopus Google Scholar) the of its in the mammalian cornea and of its and J. 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