Submitted on January 16, 2008
Revised on March 10, 2008
Accepted on March 14, 2008
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
Ophthalmology, Saint Louis University School of Medicine, Saint Louis, MO 63104-1540
Corresponding Author: fliesler{at}slu.edu
Smith-Lemli-Opitz syndrome (SLOS) is caused by an inherited defect in the last step in cholesterol biosynthesis, leading to abnormal accumulation of 7-dehydrocholesterol (7DHC) and decreased cholesterol (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 one 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 vs. control rats. However, at three 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 (DPH) exhibited decreased rotational motion and increased orientational order in ROS membranes from three-month old AY9944-treated rats, relative to controls. No significant changes in protein:lipid ratios were observed; however, rhodopsin regenerability was compromised by three months of treatment. These findings are consistent with reduced ROS membrane fluidity in the SLOS rat model, relatively to controls, primarily due to the dramatic reduction in membrane DHA levels, rather than altered sterol composition.
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