Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1)

PloS One
Natalia MastIrina Pikuleva

Abstract

Cytochrome P450 46A1 (CYP46A1) converts cholesterol to 24-hydroxycholesterol and thereby controls the major pathways of cholesterol removal from the brain. Cyp46a1-/- mice have a reduction in the rate of cholesterol biosynthesis in the brain and significant impairments to memory and learning. To gain insights into the mechanisms underlying Cyp46a1-/- phenotype, we used Cyp46a1-/- mice and quantified their brain sterol levels and the expression of the genes pertinent to cholesterol homeostasis. We also compared the Cyp46a1-/- and wild type brains for protein phosphorylation and ubiquitination. The data obtained enable the following inferences. First, there seems to be a compensatory upregulation in the Cyp46a1-/- brain of the pathways of cholesterol storage and CYP46A1-independent removal. Second, transcriptional regulation of the brain cholesterol biosynthesis via sterol regulatory element binding transcription factors is not significantly activated in the Cyp46a1-/- brain to explain a compensatory decrease in cholesterol biosynthesis. Third, some of the liver X receptor target genes (Abca1) are paradoxically upregulated in the Cyp46a1-/- brain, possibly due to a reduced activation of the small GTPases RAB8, CDC42, and RAC as a...Continue Reading

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Citations

Jul 10, 2019·Brain : a Journal of Neurology·Radhia KacherSandrine Betuing
May 8, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Alexey M PetrovIrina A Pikuleva
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Jun 28, 2019·ACS Chemical Neuroscience·Thiago C Genaro-MattosKároly Mirnics

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Methods Mentioned

BETA
ubiquitination
PCR
protein assay
GTPases
nucleotide exchange

Software Mentioned

Sequest XCorr
GeneAnalytics ( LifeMap Sciences )
Sequest
SIEVE
Proteome Discoverer
Pinpoint
GeneAnalytics
qPrimerDepot
MassHunter
Image Studio

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