DHCEO Accumulation is a Critical Mediator of Pathophysiology in a Smith-Lemli-Opitz Syndrome Model

Overview

Journal Neurobiol Dis

Specialty Neurology

Date 2011 Dec 21

PMID 22182693

Citations 54

Authors

Libin Xu

Karoly Mirnics

Aaron B Bowman

Wei Liu

Jennifer Da

Ned A Porter

Zeljka Korade

Affiliations

Soon will be listed here.

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.

Citing Articles

Assessing Postnatal Mortality in Smith-Lemli-Opitz Syndrome.

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Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome.

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Enhancing 7-dehydrocholesterol suppresses brain ferroptosis and tissue injury after neonatal hypoxia-ischemia.

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References

Caruso P, Poussaint T, Tzika A, Zurakowski D, Astrakas L, Elias E . MRI and 1H MRS findings in Smith-Lemli-Opitz syndrome. Neuroradiology. 2003; 46(1):3-14. DOI: 10.1007/s00234-003-1110-1. View

Korade Z, Mirnics K . Gene expression: The autism disconnect. Nature. 2011; 474(7351):294-5. DOI: 10.1038/474294a. View

Waage-Baudet H, Dunty Jr W, Dehart D, Hiller S, Sulik K . Immunohistochemical and microarray analyses of a mouse model for the smith-lemli-opitz syndrome. Dev Neurosci. 2005; 27(6):378-96. DOI: 10.1159/000088453. View

Kriegstein A, Dichter M . Morphological classification of rat cortical neurons in cell culture. J Neurosci. 1983; 3(8):1634-47. PMC: 6564534. View

Jiang X, Wassif C, Backlund P, Song L, Holtzclaw L, Li Z . Activation of Rho GTPases in Smith-Lemli-Opitz syndrome: pathophysiological and clinical implications. Hum Mol Genet. 2010; 19(7):1347-57. PMC: 2838542. DOI: 10.1093/hmg/ddq011. View

Tierney E, Nwokoro N, Kelley R . Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome. Ment Retard Dev Disabil Res Rev. 2000; 6(2):131-4. DOI: 10.1002/1098-2779(2000)6:2<131::AID-MRDD7>3.0.CO;2-R. View

Xu L, Korade Z, Porter N . Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies. J Am Chem Soc. 2010; 132(7):2222-32. PMC: 2839323. DOI: 10.1021/ja9080265. View

Korade Z, Mi Z, Portugal C, Schor N . Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain. Neurobiol Aging. 2006; 28(10):1522-31. DOI: 10.1016/j.neurobiolaging.2006.06.026. View

Mueller C, Patel S, Irons M, Antshel K, Salen G, Tint G . Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease. Am J Med Genet A. 2003; 123A(1):100-6. PMC: 1201564. DOI: 10.1002/ajmg.a.20491. View

10.

Irons M, Elias E, Salen G, Tint G, Batta A . Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet. 1993; 341(8857):1414. DOI: 10.1016/0140-6736(93)90983-n. View

11.

Wassif C, Zhu P, Kratz L, Krakowiak P, Battaile K, Weight F . Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome. Hum Mol Genet. 2001; 10(6):555-64. DOI: 10.1093/hmg/10.6.555. View

12.

Xu L, Davis T, Porter N . Rate constants for peroxidation of polyunsaturated fatty acids and sterols in solution and in liposomes. J Am Chem Soc. 2009; 131(36):13037-44. PMC: 3656724. DOI: 10.1021/ja9029076. View

13.

Dietschy J, Turley S . Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001; 12(2):105-12. DOI: 10.1097/00041433-200104000-00003. View

14.

Fitzky B, Moebius F, Asaoka H, Waage-Baudet H, Xu L, Xu G . 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest. 2001; 108(6):905-15. PMC: 200927. DOI: 10.1172/JCI12103. View

15.

Korade Z, Xu L, Shelton R, Porter N . Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome. J Lipid Res. 2010; 51(11):3259-69. PMC: 2952566. DOI: 10.1194/jlr.M009365. View

16.

Jiang X, Backlund P, Wassif C, Yergey A, Porter F . Quantitative proteomics analysis of inborn errors of cholesterol synthesis: identification of altered metabolic pathways in DHCR7 and SC5D deficiency. Mol Cell Proteomics. 2010; 9(7):1461-75. PMC: 2938083. DOI: 10.1074/mcp.M900548-MCP200. View

17.

SHOLL D . Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat. 1953; 87(4):387-406. PMC: 1244622. View

18.

Xu L, Korade Z, Rosado J, Liu W, Lamberson C, Porter N . An oxysterol biomarker for 7-dehydrocholesterol oxidation in cell/mouse models for Smith-Lemli-Opitz syndrome. J Lipid Res. 2011; 52(6):1222-1233. PMC: 3090243. DOI: 10.1194/jlr.M014498. View