Autism is a neurodevelopmental disorder of complex etiology. Emerging evidence suggests that low cholesterol levels due to defective cholesterol synthesis may play a role in the pathogenesis of autism or autism spectrum disorder (ASD). Cholesterol biosynthesis is essential for brain development because, in contrast to most other organs, the brain relies on the in situ synthesis of cholesterol from the early embryonic stage. Thus, deficiency in cholesterol production in the brain during embryogenesis may lead to faulty neurodevelopment. The example of this type of neurodevelopmental defects is well characterized by the genetic disorders of cholesterol biosynthesis, but the underlying mechanism of deficient cholesterol synthesis in abnormal neurodevelopment is unclear. The role of cholesterol in the organization and function of lipid rafts, the specialized structural and functional domains in cell membranes, is a fundamental question in biology. Brain cholesterol biosynthetic defects may lead to disorganization of lipid rafts in developing brain, and cause brain abnormalities. In this proposed study, the investigators will delineate the effects of cholesterol biosynthetic defects on the organization of lipid rafts in the developing brain and the associated pathophysiological consequences. To address these questions, they will employ the mouse models of 3?-hydroxysterol-?24 reductase (Dhcr24) and 3?- hydroxysterol-?7 reductase (Dhcr7) deficiencies, because these two models represent disruption of two obligatory pathways of post-squalene cholesterol synthesis. In preliminary experiments, the investigators have found that 1) either Dhcr7 or Dhcr24 disruption can cause defective formation of lipid rafts, but consequences are different, with precursor sterol-enriched raft domains in the former and sterol-depleted raft domains in the latter;2) the partitioning of sterols and raft-associated proteins into raft membranes were associated with the expression of Dhcr24, suggesting that Dhcr24 protein may play an important role in the formation and/or traffic of raft membranes. In order to develop an integrated understanding of lipid raft formation in the developing brain and to identify the potential disease-associated biomarkers and disturbed pathways, the investigators propose to conduct comprehensive analyses of the raft protein and lipid compositions in Dhcr24-/- and Dhcr7-/- brains by quantitative proteomics and lipidomics approaches. The proposed research will help to gain further insight into the mechanisms of the membrane defects caused by disruption of cholesterol biosynthesis, and also will shed new light on the potential role of more subtle abnormalities in cholesterol synthesis in ASD.

Public Health Relevance

The role of cholesterol biosynthesis in brain development and function is a fundamental question in biology, with significant implications for human disease, including autism spectrum disorder (ASD). Both Dhcr24- and Dhcr7-deficient mice represent the natural models of cholesterol synthetic defects with membrane abnormalities and, therefore, as the genetic models for understanding of cholesterol biosynthesis disorders in humans, mice lacking Dhcr7 and Dhcr24 should be useful in the study of the role of brain cholesterol in ASD.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Pediatrics Subcommittee (CHHD)
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Kau, Alice S
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Medical College of Wisconsin
Schools of Medicine
United States
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Tint, G S; Pan, Luxing; Shang, Quan et al. (2014) Desmosterol in brain is elevated because DHCR24 needs REST for Robust Expression but REST is poorly expressed. Dev Neurosci 36:132-42
Ljungqvist, A; Feng, D M; Hook, W et al. (1988) Antide and related antagonists of luteinizing hormone release with long action and oral activity. Proc Natl Acad Sci U S A 85:8236-40
Ljungqvist, A; Folkers, K (1988) The reaction of pyridinecarboxylic acids with dicyclohexylcarbodiimide and p-nitrophenol. Acta Chem Scand B 42:408-10
Ljungqvist, A; Feng, D M; Tang, P F et al. (1987) Design, synthesis and bioassays of antagonists of LHRH which have high antiovulatory activity and release negligible histamine. Biochem Biophys Res Commun 148:849-56