DHCEO accumulation is a critical mediator of pathophysiology in a Smith-Lemli-Opitz syndrome model.

Xu L, Mirnics K, Bowman AB, Liu W, Da J, Porter NA, Korade Z
Neurobiol Dis. 2012 45 (3): 923-9

PMID: 22182693 · PMCID: PMC3674775 · DOI:10.1016/j.nbd.2011.12.011

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of metabolism caused by defective cholesterol biosynthesis. Mutations within the gene encoding 7-dehydrocholesterol reductase (DHCR7), the last enzyme in the pathway, lead to the accumulation of 7-dehydrocholesterol (7-DHC) in the brain tissue and blood of the SLOS patients. The objective of this study was to determine the consequences of the accumulation of an immediate cholesterol precursor, 7-DHC and its oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), in the brain tissue of Dhcr7-KO mouse, a model for SLOS. We found that cholesterol, 7-DHC and DHCEO show region-specific distribution, suggesting that the midbrain and the cortex are the primary sites of vulnerability. We also report that neurons are ten fold more susceptible to a 7-DHC-derived oxysterol mixture than glial cells, and that DHCEO accelerates differentiation and arborization of cortical neurons. The overall results suggest that 7-DHC oxidative metabolites are critical contributors to altered neural development in SLOS. The future studies will test if antioxidant supplementation will ameliorate some of the clinical symptoms associated with this devastating disease.

Copyright © 2011 Elsevier Inc. All rights reserved.

MeSH Terms (18)

Animals Astrocytes Brain Cells, Cultured Cell Survival Cholestenones Chromatography, High Pressure Liquid Dehydrocholesterols Disease Models, Animal Dose-Response Relationship, Drug Embryo, Mammalian Mice Mice, Knockout Nerve Tissue Proteins Neurons Oxidoreductases Acting on CH-CH Group Donors Smith-Lemli-Opitz Syndrome Tandem Mass Spectrometry

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