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Analysis of Translation in the Developing Mouse Brain using Polysome Profiling
Published on: May 22, 2021
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Desmosterolosis and desmosterol homeostasis in the developing mouse brain
Luke B Allen1, Thiago C Genaro-Mattos2, Ned A Porter3
1Department of Pediatrics, Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Journal of Inherited Metabolic Disease
|March 21, 2019
Summary
Mutations in the DHCR24 enzyme cause desmosterolosis, where desmosterol replaces cholesterol in the brain. This study reveals elevated desmosterol in Dhcr24 mutant mice, impacting brain development and gene expression.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Cholesterol is vital for brain development and cellular function.
- The brain synthesizes its own cholesterol from precursors like desmosterol.
- DHCR24 enzyme mutations cause desmosterolosis, a developmental disorder.
Purpose of the Study:
- To analyze brain sterol content (desmosterol, 7-DHC, cholesterol) during development and adulthood.
- To investigate the consequences of Dhcr24 mutations in a mouse model of desmosterolosis.
- To compare desmosterolosis with Smith-Lemli-Opitz syndrome.
Main Methods:
- High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for sterol analysis.
- Analysis of gene expression (lipids, sterols, nuclear receptors, synaptic plasticity).
- Assessment of neuronal morphology and brain anatomy in Dhcr24 mutant mice.
Main Results:
- Desmosterol almost entirely replaced cholesterol in Dhcr24-KO mouse brains by postnatal day 0.
- Elevated desmosterol levels persisted into adulthood in both knockout and heterozygous Dhcr24 mice.
- Dhcr24 mutations led to altered gene expression and increased neuronal arborization.
Conclusions:
- DHCR24 deficiency drastically alters brain sterol composition, with desmosterol accumulation.
- Desmosterolosis shares pathophysiological mechanisms with Smith-Lemli-Opitz syndrome.
- DHCR24 mutations impact brain development, gene expression, and neuronal structure.
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