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Journal of Lipid Research, Vol. 49, 1488-1499, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Alteration of retinal rod outer segment membrane fluidity in a rat model of Smith-Lemli-Opitz syndrome^*

Kathleen Boesze-Battaglia^*, Monika Damek-Poprawa^*, Drake C. Mitchell, Laura Greeley, Richard S. Brush^,, Robert E. Anderson^,**,, Michael J. Richards and Steven J. Fliesler^1,,***

^* From the Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104
the Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892
the Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
^** the Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
Dean McGee Eye Institute, Oklahoma City, OK 73104
the Department of Ophthalmology (Saint Louis University Eye Institute), Saint Louis University School of Medicine, St. Louis, MO 63104
^*** the Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104

^* This study was supported by United States Public Health System, National Institutes of Health Grants EY-007361 (S.J.F.), EY-00871 (R.E.A.), EY-04149 (R.E.A.), EY-10420 (K.B-B.), EY-12190 (R.E.A.), and RR-17703 (R.E.A); the Foundation Fighting Blindness (R.E.A.); and unrestricted departmental grants from Research to Prevent Blindness (S.J.F. and R.E.A.). K.B-B. is the recipient of an E. Matilda Ziegler Vision Award. S.J.F. is the recipient of a Research to Prevent Blindness Senior Scientific Investigator Award.

Published, JLR Papers in Press, March 14, 2008.

¹ To whom correspondence should be addressed. e-mail: fliesler{at}slu.edu

Smith-Lemli-Opitz syndrome (SLOS) is caused by an inherited defect in the last step in cholesterol (Chol) biosynthesis, leading to abnormal accumulation of 7-dehydrocholesterol and decreased Chol levels. Progressive retinal degeneration occurs in an animal model of SLOS, induced by treating rats with AY9944, a selective inhibitor of the enzyme affected in SLOS. Here we evaluated alterations in the biochemical and physical properties of retinal rod outer segment (ROS) membranes in this animal model. At 1 month of AY9944 treatment, there were modest alterations in fatty acid composition, but no significant differences in cis-parinaric acid (cPA) spectroscopic parameters in ROS membranes from treated versus control rats. However, at 3 months, ROS docosahexaenoic acid (DHA) content was dramatically reduced, and cPA fluorescence anisotropy values were decreased, relative to controls. Also, 1,6-diphenyl-1,3,5-hexatriene exhibited decreased rotational motion and increased orientational order in ROS membranes from 3 month-old AY9944-treated rats, relative to controls. No significant changes in protein:lipid ratios were observed; however, rhodopsin regenerability was compromised by 3 months of treatment. These findings are consistent with reduced ROS membrane fluidity in the SLOS rat model, relative to controls, primarily due to the dramatic reduction in membrane DHA levels, rather than altered sterol composition.

Supplementary key words fluorescence polarization • cis-parinaric acid • diphenylhexatriene • fatty acid • retina • AY9944

Abbreviations: 7DHC, 7-dehydrochosterol; BRD, Brownian rotational diffusion; Chol, cholesterol; cPA, cis-parinaric acid; DHA, docosahexaenoic acid; DPH, 1,6-diphenyl-1,3,5-hexatriene; mAb, monoclonal antibody; ROS, rod outer segment; SLOS, Smith-Lemli-Opitz syndrome

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