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N. Lassen, B.J. Bateman, T. Estey, J.R. Kuszak, J. Piatigorsky, G. Duester, V. Vasiliou; Cataract Phenotype in Aldh1a1–/–/aldh3a1–/– Double Knockout Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4105.
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© ARVO (1962-2015); The Authors (2016-present)
The aldehyde dehydrogenases ALDH3A1 and ALDH1A1 are expressed at high concentrations in the cornea and lens of the mammalian eye. Our long standing hypothesis is that these proteins protect the eye against environmentally–induced corneal injury and cataract formation. To test this hypothesis we have developed an Aldh1a1–/–/Aldh3a1–/– double knockout mouse line in order to examine possible structural and functional changes in the eyes of these mice.
Single and double knockout mice were evaluated for structural changes in the cornea and lens by slit lamp biomicroscopy and scanning electron microscopy. The expression of several antioxidant enzymes (i.e. catalase and Cu–Zn superoxide dismutase), aldehyde–detoxification enzymes (i.e. alcohol dehydrogenase and aldose reductase) and other corneal crystallins were studied in all genetic stocks by Western blot analysis. The chymotrypsin–like activity of the proteasome was evaluated using a fluorogenic substrate in all mice. Finally, 4–hydroxy–2–nonenal (4–HNE)– and malondialdehyde (MDA)–adducted proteins were detected by Western blotting.
Aldh1a1–/–/Aldh3a1–/––deficient mice exhibited corneal abnormalities detected by scanning electron microscopy. In addition, these mice developed lens opacification in the anterior and posterior subcapsular regions as well as punctuate opacities in the cortex that were detected by slit lamp biomicroscopy. No changes in the expression pattern of these proteins were found in either cornea or lens of double knockout mice compared to wild type animals. Significant inhibition of the chymotrypsin–like activity of the proteasome as well as an increase in 4–HNE– and MDA–protein adducts were observed in the double knockout mice compared to the wild type mice.
These findings support a novel function for ALDH3A1 and ALDH1A1 in the protection of proteasome activity by metabolizing toxic aldehydes produced during lipid peroxidation. The double knockout mouse line we generated highlights the importance of ALDH1A1 and ALDH3A1 in corneal and lens physiology and provides a valuable model to study the combined roles of these enzymes in clinically–significant diseases of both cornea and lens.
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