Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome: Thinking Beyond Cholesterol Deficiency

Abstract

Smith-Lemli-Opitz Syndrome (SLOS) is a recessive hereditary disease caused by a defect in the last step in cholesterol biosynthesis— the reduction of the Δ7 double bond of 7-dehydrocholesterol (7DHC)— resulting in the abnormal accumulation of 7DHC and diminished levels of Chol in all bodily tissues. Treatment of rats with AY9944— a drug that inhibits the same enzyme that is genetically defective in SLOS (i.e., DHCR7, 3β-hydroxysterol-Δ7-reductase)— starting in utero and continuing throughout postnatal life, provides a convenient animal model of SLOS for understanding the disease mechanism and also for testing the efficacy of therapeutic intervention strategies. Herein, the biochemical, morphological, and electrophysiological hallmarks of retinal degeneration in this animal model are reviewed. A high-cholesterol diet partially ameliorates the associated visual function deficits, but not the morphological degeneration. Recent studies using this model suggest that the disease mechanism in SLOS goes well beyond the initial cholesterol pathway defect, including global metabolic alterations, lipid and protein oxidation, and differential expression of hundreds of genes in multiple ontological gene families. These findings may have significant implications with regard to developing more optimal therapeutic interventions for managing SLOS patients.

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

“…Whereas control populations show plasma cholesterol levels of ‫ف‬ 180 mg/dl and 7-DHC of ‫ف‬ 0.005-0.05 mg/dl, SLOS patients can have plasma cholesterol levels of ‫ف‬ 85 mg/dl or lower and 7-DHC levels as high as ‫ف‬ 25 mg/dl ( 20,28 ). A rough calculation of the kinetics of oxysterol product Indeed, our studies are in agreement with a recent proposal by Fliesler ( 63 ) suggesting that SLOS is not only an imbalance of cholesterol and 7-DHC caused by defects in Dhcr7, but it also involves secondary defects in nonsterol metabolic pathways and additional biochemical changes ( 63 ). Low levels of cholesterol are present in several disorders arising from defects in different enzymes in the cholesterol biosynthesis pathway (CDPX2, lathosterolosis, desmosterolosis) ( 18,64 ).…”

Ion-current-based Proteomic Profiling of the Retina in a Rat Model of Smith-Lemli-Opitz Syndrome

“…7A). As the ONL normally contains the nuclei of only the rod and cone photoreceptor cells, these findings are consistent with the observed retinal degeneration in the SLOS rat model (12,38). Notably, TUNELpositive labeling was restricted almost exclusively to the ONL, suggesting that photoreceptor cells are somehow selectively (or more highly) sensitive to the associated cytotoxic effects of AY9944 treatment.…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…7DHC cannot substitute for result in oxidation of lipids and proteins in addition to cholesterol. This occurs in the AY9944 rat model and has been proposed to contribute to the pathology of SLOS ( 126,166 ). Additional work is necessary to establish the extent to which either oxidative stress or oxysterols functionally underlie or contribute to the pathology of SLOS.…”