The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Petrov, Alexey M.; Mast, Natalia; Li, Yong; Pikuleva, Irina A.

doi:10.1096/fj.201900092r

Cited by 24 publications

(42 citation statements)

References 178 publications

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“…One of the reported phenotypes of CH24H-KO mice is an impairment in learning 47 . Conversely, it has been reported that activation of CH24H has pro-cognitive potential 20,48 . Three-month-old APP/PS1-Tg animals were treated with soticlestat and underwent the Y-maze test.…”

Section: Discussionmentioning

confidence: 95%

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Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Nishi

Kondo

Miyamoto

et al. 2020

Sci Rep

104

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Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

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Section: Discussionmentioning

confidence: 95%

“…S7). This observation may disagree with the cognitive benefits of efavirenz, a reverse transcriptase inhibitor known for CH24H activation 20,48 . It should be noted that the effects of efavirenz on cognition are apparently associated with improvement in amyloid pathology.…”

Section: Discussionmentioning

confidence: 96%

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Nishi

Kondo

Miyamoto

et al. 2020

Sci Rep

104

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“…Studies in mice revealed a broad therapeutic potential of increased CYP46A1 activity for various neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases, Niemann-Pick disease type C and spinocerebellar ataxia ( Hudry et al , 2010 ; Burlot et al , 2015 ; Boussicault et al , 2016 ; Mast et al , 2017 b ; Kacher et al , 2019 ; Mitroi et al , 2019 ; Nóbrega et al , 2019 ; Petrov et al , 2019 b ). Even glioblastoma, an aggressive brain tumour, was found to be inhibited in mice by pharmacologic CYP46A1 activation ( Han et al , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…The effects on the amyloid β levels (Aβ) were the treatment paradigm-specific, either Aβ decreasing or not changing. Studies by the omics approaches documented altered protein phosphorylation in EFV-treated 5XFAD mice and pointed to the effects on synaptic function, inflammation, microglia phenotype, oxidative stress, cellular hypoxia, ubiquitin-proteasome system, autophagy and apoptosis ( Petrov et al , 2019 b ). Protein phosphorylation was also altered in Cyp46a1 −/− mice ( Mast et al , 2017 a ), and the affected processes overlapped in part with those in EFV-treated 5XFAD mice (synaptic transmission, ubiquitination and cytoskeleton maintenance).…”

Section: Introductionmentioning

confidence: 99%

Brain sterol flux mediated by cytochrome P450 46A1 affects membrane properties and membrane-dependent processes

Petrov

Mast

et al. 2020

Brain Communications

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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 behavioural 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 versus control 5XFAD mice. Incubation of synaptosomal fractions with the inhibitors of glycogen synthase kinase 3, cyclin-dependent kinase 5, protein phosphatase 1/2 A, and protein phosphatase 2B revealed that increased sterol flux in efavirenz-treated versus control 5XFAD mice affected the ability of all four enzymes to modulate glutamate release. In contrast, in Cyp46a1−/− versus 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.

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“…appear to lend anti-apoptotic activities to these lipoproteins Previous studies reported both pro-and anti-apoptotic effects of 24-OHC(55)(56)(57)(58)(59). Possibly, the discrepant findings are due to differences in concentrations (micromolar vs. nanomolar) or the origin (endogenously produced vs. exogenously supplied) of the oxysterol in the various cell culture models.…”

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confidence: 99%

HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

Yalçinkaya

Kerksiek

Gebert

et al. 2020

Journal of Lipid Research

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Loss of pancreatic β-cell mass and function as a result of sustained endoplasmic reticulum (ER) stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca 2+ -ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the hedgehog signaling receptor Smoothened (Smo) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced βcell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (24-OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and-in cells lacking ATP-binding cassette transporter ABCG1 or the 24-OHC synthesizing enzyme CYP46A1-restored the protective activity of HDL. Inhibition of Smo countered the beneficial effects of HDL but also LDL, and Smo agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the Smo-activated transcription factor gliomaassociated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation and mobilization of oxysterols for activation of the hedgehog signalling receptor Smo.

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The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Cited by 24 publications

References 178 publications

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Brain sterol flux mediated by cytochrome P450 46A1 affects membrane properties and membrane-dependent processes

HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

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