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J. Biol. Chem., Vol. 282, Issue 35, 25668-25676, August 31, 2007

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Multiple and Additive Functions of ALDH3A1 and ALDH1A1

CATARACT PHENOTYPE AND OCULAR OXIDATIVE DAMAGE IN Aldh3a1(-/-)/Aldh1a1(-/-) KNOCK-OUT MICE^*

Natalie Lassen, J. Bronwyn Bateman, Tia Estey, Jer R. Kuszak^¶, David W. Nees^||, Joram Piatigorsky^||, Gregg Duester^**, Brian J. Day, Jie Huang, Lisa M. Hines, and Vasilis Vasiliou¹

From the Molecular Toxicology and Environmental Health Sciences Program, Departments of Pharmaceutical Sciences, and Ophthalmology and Pediatrics, Rocky Mountain Lions Eye Institute, The Children's Hospital, University of Colorado, Denver, Colorado 80262, the ^¶Departments of Ophthalmology and Pathology, Rush University Medical Center, Chicago, Illinois 60612, the ^||Laboratory of Molecular and Developmental Biology, NEI, National Institutes of Health, Bethesda, Maryland 20892, the ^**OncoDevelopmental Biology Program, Burnham Institute, La Jolla, California 92037, the Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, and the Department of Biology, University of Colorado, Colorado Springs, Colorado 80933

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.

Received for publication, March 9, 2007 , and in revised form, May 22, 2007.

^* This work was supported by National Institutes of Health Grants EY11490 (to V. V.), EY08282 (to J. B. B.), and EY13969 (to G. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Figs. 1–4.

¹ To whom correspondence should be addressed: Molecular Toxicology and Environmental Health Sciences Program, Dept. of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Denver, CO 80262. Tel.: 303-315-6153; Fax: 303-315-6281; E-mail: vasilis.vasiliou{at}uchsc.edu.

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