Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease presenting with multiple congenital anomalies, caused by a defect in cholesterol biosynthesis that results in abnormally elevated levels of 7-dehydrocholesterol (7DHC). Progressive retinal degeneration has been demonstrated in a rat model of SLOS, which is markedly exacerbated by intense light, far more so than occurs in normal albino rats under the same conditions. Herein, we demonstrate that, by six postnatal weeks, retinas in the SLOS rat model contain levels of lipid hydroperoxides (LPOs) comparable to those found in light-damaged albino rats (twice the normal steady-state levels), and that intense light exposure results in a three-fold elevation of LPOs with concomitant severe retinal degeneration. These results suggest a correlation between retinal degeneration and LPO levels. We propose that the presence of 7DHC in the SLOS rat retina potentiates LPO formation, and promotes the observed hypersensitivity to light-induced retinal degeneration. KeywordsAY9944; Smith-Lemli-Opitz syndrome; retina; degeneration; light damage; lipid hydroperoxide; rat Retinal degenerations resulting either from hereditary or exogenous causes are thought to entail molecular events that, in part, involve oxidative damage to lipids, proteins, and/or nucleic acids, resulting in cellular dysfunction and, ultimately, cell death. Such events are known to be potentiated by exposure to intense light (Organisciak and Winkler, 1994;Boulton et al., 2001;Glickman, 2002;Wenzel et al., 2005). Certain metabolic conditions result in the formation of pro-oxidant molecules, the presence of which can promote cellular degeneration and death. The Smith-Lemli-Opitz syndrome (SLOS) likely represents such a condition. SLOS, the first described 'multiple congenital anomalies syndrome ' (Smith et al., 1964; cf. Porter, 2000;Jira et al., 2003), is also the first member of a growing family of inborn errors of anabolic metabolism involving defective cholesterol biosynthesis (Kelley, 2000;Porter, 2003). SLOS specifically is due to a defect in 3β-hydroxysterol-Δ 7 -reductase (Waterham and Wanders, 2000;Correa-Cerro and Porter, 2005), resulting in abnormal and excessive accumulation of the cholesterol precursor, 7-dehydrocholesterol (7DHC) (Tint et al., 1994 cf. Fliesler, 2002).We have previously demonstrated a progressive retinal degeneration in a pharmacologically induced rat model of SLOS (Fliesler et al., 2004). More recently, we showed that intense light exposure markedly exacerbates that retinal degeneration, whereas treatment of rats with dimethylthiourea, a hydroxyl radical scavenger and anti-oxidant, prior to light exposure largely protects against the enhancement of degeneration (Vaughan et al., 2005), implicating a free radical mechanism in the degeneration. Herein, we provide evidence that correlates the severity of retinal degeneration in the SLOS rat model, relative to normal albino rats, with accumulated levels of lipid hydroxperoxides (LPOs) in the retina, particu...

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

“…Photoreceptor outer segment membranes are highly enriched in PUFA (32). We have shown recently (18,19) that: a) the SLOS rat model is more susceptible to intense light-induced retinal degeneration than normal albino rats; b) the histologic damage correlates with levels of lipid peroxides; c) ERG deficits and levels of lipid peroxides in retinas of SLOS rats under normal ambient lighting conditions are comparable to those in retinas of light-damaged (but otherwise normal) albino rats; and d) pretreatment of rats with a free radical scavenger (dimethylthiourea) affords substantial protection from light-induced retinal damage in both normal albino and SLOS rats. In fact, lipid peroxidation has been linked to retinal photodamage by other investigators (33)(34)(35).…”

“…Taken together, these findings predict that SLOS has an associated retinal degeneration involving biochemical, histologic, and functional abnormalities in rods and cones. Furthermore, constant bright light exposure exacerbates photoreceptor degeneration in the rat SLOS model (18), far more so than in normal, age-matched albino rats, and the severity of the histologic degeneration correlates with the levels of lipid hydroperoxides present in the retina (19).…”

Probing lipid-protein adduction with alkynyl surrogates: application to Smith-Lemli-Opitz syndrome

“…1 H and 13 C NMR spectra were collected on a 300 or 400 MHz NMR. High-resolution mass spectrometry (HRMS) analyses were carried out at the University of Notre Dame.…”

Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome

“…After the appropriate time in mechanisms. One hypothesis is that 7-DHC and/or its oxidative derivatives, i.e., oxysterols, are biologically active, which may play some role in the pathology of SLOS ( 19,(21)(22)(23)(24). In one recent study, for example, it was reported that high levels of 7-DHC cause exaggerated photosensitivity to ultraviolet (UV) A for SLOS patients ( 24 ).…”