Sterol biosynthesis, brain development, and disease

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Abstract

Cholesterol biosynthesis is indispensable for CNS development and function. The developing brain relies almost entirely on intrinsic sterol synthesis to support membrane biogenesis, axonal outgrowth, synaptogenesis, and myelination. Pathogenic variants in sterol biosynthetic enzymes, including DHCR7 and DHCR24, result in complex neurodevelopmental disorders such as Smith-Lemli-Opitz syndrome and desmosterolosis. In addition to cholesterol-lowering drugs (statins), some other pharmacological agents such as antipsychotics, antidepressants, and beta blockers can also inhibit cholesterol biosynthesis due to off-target effects. This inhibition produces dual pathophysiological effects: cholesterol depletion and accumulation of its precursor, 7-dehydrocholesterol, an exceptionally oxidizable molecule that spontaneously generates toxic oxysterols. Given the intense demand for cholesterol synthesis in the developing brain, prenatal exposure to sterol biosynthesis–inhibiting medications may have far-reaching effects. In this Review, we describe convergent biochemical, genetic, and epidemiologic data that implicate developmental sterol dysregulation as a modifiable risk factor for neurodevelopmental pathology and underscore the urgent need for routine sterol pathway safety assessment in drug development and prenatal pharmacotherapy.

Authors

Eric S. Peeples, Zeljka Korade, Karoly Mirnics