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

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 result of a reduced phosphorylation of RAB3IP and PAK1. Fourth, the phosphorylation of many other proteins (a total of 146) is altered in the Cyp46a1-/- brain, including microtubule associated and neurofilament proteins (the MAP and NEF families) along with proteins related to synaptic vesicles and synaptic neurotransmission (e.g., SLCs, SHANKs, and BSN). Fifth, the extent of protein ubiquitination is increased in the Cyp46a1-/- brain, and the affected proteins pertain to ubiquitination (UBE2N), cognition (STX1B and ATP1A2), cytoskeleton function (TUBA1A and YWHAZ), and energy production (ATP1A2 and ALDOA). The present study demonstrates the diverse potential effects of CYP46A1 deficiency on brain functions and identifies important proteins that could be affected by this deficiency.

SUBMITTER: Mast N

PROVIDER: S-EPMC5658173 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Mast Natalia N Lin Joseph B JB Anderson Kyle W KW Bjorkhem Ingemar I Pikuleva Irina A IA

PloS one 20171026 10

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. W ...[more]

PMID: 29073233

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Project description:Cytochrome P450 46A1 encoded by CYP46A1 catalyzes cholesterol 24-hydroxylation and is a CNS-specific enzyme that controls cholesterol removal and turnover in the brain. Accumulating data suggest that increases in cytochrome P450 46A1 activity in mouse models of common neurodegenerative diseases affect various, apparently unlinked biological processes and pathways. Yet, the underlying reason for these multiple enzyme activity effects is currently unknown. Herein, we tested the hypothesis that cytochrome P450 46A1-mediated sterol flux alters physico-chemical properties of the plasma membranes and thereby membrane-dependent events. We used 9-month old 5XFAD mice (an Alzheimer's disease model) treated for 6 months with the anti-HIV drug efavirenz. These animals have previously been shown to have improved behavioral performance, increased cytochrome P450 46A1 activity in the brain, and increased sterol flux through the plasma membranes. We further examined 9-month old Cyp46a1 -/- mice, which have previously been observed to have cognitive deficits and decreased sterol flux through brain membranes. Synaptosomal fractions from the brain of efavirenz-treated 5XFAD mice had essentially unchanged cholesterol levels as compared to control 5XFAD mice. However with efavirenz treatment in these mice, there were changes in the membrane properties (increased cholesterol accessibility, ordering, osmotic resistance, and thickness) as well as total glutamate content and ability to release glutamate in response to mild stimulation. Similarly, the cholesterol content in synaptosomal fractions from the brain of Cyp46a1 -/- mice was essentially the same as in wild type mice but knockout of Cyp46a1 was associated with changes in membrane properties and glutamate content and its exocytotic release. Changes in Cyp46a1 -/- mice were in the opposite direction to those observed in efavirenz-treated vs control 5XFAD mice. Incubation of synaptosomal fractions with the inhibitors of glycogen synthase kinase 3, cyclin-dependent kinase 5, protein phosphatase 1/2A or calcineurin, and protein phosphatase 2B revealed that increased sterol flux in efavirenz-treated vs control 5XFAD mice affected the ability of all four enzymes to modulate glutamate release. In contrast, in Cyp46a1 -/- vs wild type mice, decreased sterol flux altered the ability of only cyclin-dependent kinase 5 and protein phosphatase 2B to regulate the glutamate release. Collectively, our results support cytochrome P450 46A1-mediated sterol flux as an important contributor to the fundamental properties of the membranes, protein phosphorylation, and synaptic transmission Also, our data provide an explanation of how one enzyme, cytochrome P450 46A1, can affect multiple pathways and processes and serve as a common potential target for several neurodegenerative disorders.

Dataset Information

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

Publications

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

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