title: DHCEO accumulation is a critical mediator of pathophysiology in a Smith-Lemli-Opitz syndrome model.
abstract: 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.
authors.affiliation: Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Libin
authors.initials: L
authors.lastname: Xu
authors.forename: Karoly
authors.initials: K
authors.lastname: Mirnics
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Da
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Korade
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D002783:Cholestenones / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003684:Dehydrocholesterols / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency / Q000378:metabolism*; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D053719:Tandem Mass Spectrometry
chemical_list: C561089:3,5-dihydroxycholest-7-en-6-one; D002783:Cholestenones; D003684:Dehydrocholesterols; D009419:Nerve Tissue Proteins; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase