TY - JOUR
T1 - DHCEO accumulation is a critical mediator of pathophysiology in a Smith-Lemli-Opitz syndrome model
AU - Xu, Libin
AU - Mirnics, Karoly
AU - Bowman, Aaron B.
AU - Liu, Wei
AU - Da, Jennifer
AU - Porter, Ned A.
AU - Korade, Zeljka
N1 - Funding Information:
The National Institutes of Health ( 1R01 MH079299 and 2R01MH067234 to K.M.; NIEHS ES0016931 to A.B.B.; NICHD HD064727 to N.A.P.) supported this work. Z.K. appreciates support from the Vanderbilt Kennedy Center for Research on Human Development. The authors thank Dr. Georges Barnes for the use of Neurolucida system.
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - 7-Dehydrocholesterol
KW - Cortical neurons
KW - DHCEO
KW - Oxysterol
KW - Smith-Lemli-Opitz syndrome
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U2 - 10.1016/j.nbd.2011.12.011
DO - 10.1016/j.nbd.2011.12.011
M3 - Article
C2 - 22182693
AN - SCOPUS:84856570361
SN - 0969-9961
VL - 45
SP - 923
EP - 929
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -