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K. Boesze–Battaglia, M.J. Richards, R.S. Brush, R.E. Anderson, S.J. Fliesler; Age–Dependent Alterations in Rod Outer Segment Membrane Properties in a Rodent Model of Smith–Lemli–Opitz Syndrome . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3739.
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© ARVO (1962-2015); The Authors (2016-present)
Prior studies have demonstrated progressive retinal degeneration in a pharmacologically induced rat model of Smith–Lemli–Opitz syndrome (SLOS), a recessive disease caused by defective cholesterol synthesis and abnormal accumulation of 7–dehydrocholesterol (7DHC). Although rod outer segment (ROS) lipid composition is dramatically abnormal by 1 mo in this model, correlative changes in rod structure and function take up to 3 mo to manifest. Here we compared age–dependent biochemical and biophysical properties of ROS membranes from SLOS rats vs. age–matched controls.
Sprague–Dawley rats were treated with AY9944, a selective inhibitor of 3ß–hydroxysterol–Δ7–reductase, as previously described (Fliesler et al., 1999, 2004). ROS membranes were isolated at 1 and 3 mo postnatal from treated and age–matched control rats, and were then analyzed for sterol and fatty acid (FA) composition, rhodopsin (Rhod) and phospholipid (PL) content, rhodopsin regenerability (with exogenous 11–cis retinal), and membrane fluidity (measuring cis–parinaric acid fluorescence anisotropy).
By 1 mo of AY9944 treatment, ROS membranes had 7DHC/cholesterol mole ratios ≈4:1 and FA composition was markedly altered (ω6/ω3 ratio increased ≈1.5–fold), yet they exhibited no appreciable changes in Rhod/PL ratio or membrane fluidity, compared to controls. However, by 3 mo of treatment, 7DHC/cholesterol ratios were >5:1; FA acid composition was further deranged (ω6/ω3 ratio increased ≈2.3–fold), the Rhod/PL mole ratio decreased >3–fold, and membrane fluidity decreased (at 37oC), relative to controls. Also, in vitro Rhod regenerability at 3 mo was significantly reduced; after 2 h and 24 h, respectively, Rhod regeneration was only ≈25% and ≈65% in ROS from AY9944–treated rats, vs. >50% and >80% in controls.
Progressive alterations in ROS membrane lipid composition, rhodopsin content and regenerability, and membrane fluidity correlate with retinal degeneration and electrophysiological dysfunction in this rat model of SLOS.
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