<scp>NPC</scp>
            1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by
            <scp>CYP</scp>
            46A1 activation

Mitroi, Daniel; Pereyra-Gómez, Guadalupe; Soto-Huelin, Beatriz; Senovilla, Fernando; Kobayashi, Toshihide; Esteban, José A.; Ledesma, María Dolores

doi:10.15252/embr.201948143

Cited by 47 publications

(45 citation statements)

References 55 publications

(107 reference statements)

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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%

“…Even glioblastoma, an aggressive brain tumour, was found to be inhibited in mice by pharmacologic CYP46A1 activation ( Han et al , 2020 ). Mechanistically, increases in CYP46A1 activity affected multiple processes and led to improvements in neurotransmission; enhancement in vesicular and endosomal trafficking; stimulation of proteasome and autophagy machineries; reduction of neuronal atrophy; and decreases in microgliosis ( Hudry et al , 2010 ; Burlot et al , 2015 ; Boussicault et al , 2016 ; Kacher et al , 2019 ; Mitroi et al , 2019 ; Nóbrega et al , 2019 ). Conversely, lack of CYP46A1 was found to elicit severe deficits in memory and learning, likely due to impaired long-term potentiation as a result of decreased protein prenylation ( Kotti et al , 2006 , 2008 ).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

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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“…CYP46A1 converts cholesterol to 24-hydroxycholesterol (24HC), a transportable form of cholesterol from the brain into the systemic circulation and a biologically active oxysterol that can interact with different proteins and receptors such as liver X receptors and N -methyl- d -aspartate receptors ( Lutjohann et al , 1996 ; Bjorkhem et al , 1998 ; Janowski et al , 1999 ; Lund et al , 1999 ; Meaney et al , 2002 ; Paul et al , 2013 ). Studies in mice showed that increases in CYP46A1 activity by genetic or pharmacologic means are beneficial in the models of Alzheimer’s and Huntington’s diseases, Niemann–Pick disease type C, spinocerebellar ataxia, depression and glioblastoma ( Hudry et al , 2010 ; Burlot et al , 2015 ; Boussicault et al , 2016 ; Mast et al , 2017b ; Patel et al , 2017 ; Han et al , 2019 ; Kacher et al , 2019 ; Mitroi et al , 2019 ; Nóbrega et al , 2019 ; Petrov et al , 2019b ). A clinical trial is on-going in people with Alzheimer’s disease to evaluate CYP46A1 activation by efavirenz (EFV), a reverse transcriptase inhibitor and anti-HIV drug (ClinicalTrials.gov, NCT03706885).…”

Section: Introductionmentioning

confidence: 99%

“…Modulation of CYP46A1 activity in animal studies was found to affect various biological processes ( Hudry et al , 2010 ; Burlot et al , 2015 ; Boussicault et al , 2016 ; Kacher et al , 2019 ; Mitroi et al , 2019 ; Nóbrega et al , 2019 ). Hence, we proposed the sterol flux hypothesis as sterol flux was a common process modulated in the brain of these animals ( Petrov et al , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

CYP46A1-dependent and independent effects of efavirenz treatment

Mast

El‐Darzi

Petrov

et al. 2020

Brain Communications

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Cholesterol excess in the brain is mainly disposed via cholesterol 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. CYP46A1 is emerging as a promising therapeutic target for various brain diseases with both enzyme activation and inhibition having a therapeutic potential. The rate of cholesterol 24-hydroxylation determines the rate of brain cholesterol turnover and the rate of sterol flux through the plasma membranes. The latter was shown to affect membrane properties and thereby membrane proteins and membrane-dependent processes. Previously we found that treatment of 5XFAD mice, an Alzheimer’s disease model, with a small dose of an anti-HIV drug efavirenz allosterically activated CYP46A1 in the brain and mitigated several disease manifestations. Herein, we generated Cyp46a1-/-5XFAD mice and treated them, along with 5XFAD animals, with efavirenz to ascertain CYP46A1-dependent and independent drug effects. Efavirenz-treated vs control Cyp46a1-/-5XFAD and 5XFAD mice were compared for the brain sterol and steroid hormone content, amyloid β burden, protein and mRNA expression as well as synaptic ultrastructure. We found that the CYP46A1-dependent efavirenz effects included changes in the levels of brain sterols, steroid hormones, and such proteins as GFAP, Iba1, Munc13-1, PSD-95, gephyrin, synaptophysin, and synapsin-1. Changes in the expression of genes involved in neuroprotection, neurogenesis, synaptic function, inflammation, oxidative stress, and apoptosis were also CYP46A1-dependent. The total amyloid β load was the same in all groups of animals, except lack of CYP46A1 decreased the production of the amyloid β40 species independent of treatment. In contrast, altered transcription of genes from cholinergic, monoaminergic, and peptidergic neurotransmission, steroid sulfation and production as well as vitamin D3 activation was the main CYP46A1-independent efavirenz effect. Collectively, the data obtained reveal that CYP46A1 controls cholesterol availability for the production of steroid hormones in the brain and the levels of biologically active neurosteroids. In addition, CYP46A1 activity also seems to affect the levels of PSD-95, the main postsynaptic density protein, possibly by altering the Camk2n1 (calcium/calmodulin dependent protein kinase II inhibitor 1) expression and activity of GSK3β (glycogen synthase kinase 3β). Even at a small dose, efavirenz likely acts as a transcriptional regulator, yet this regulation may not necessarily lead to functional effects. This study further confirmed that CYP46A1 is a key enzyme for cholesterol homeostasis in the brain and that the therapeutic efavirenz effects on 5XFAD mice are likely realized via CYP46A1 activation.

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“…Additionally, the plasticity of excitatory synaptic transmission has been described as impaired. In neocortical neurons impaired long-term potentiation and in Purkinje cells impaired long-term depression have been found in NPC1-deficient mice [8,21,22]. In the hippocampal CA1 region AMPA has been observed to fail to decrease field potentials [23].…”

Section: Discussionmentioning

confidence: 99%

Alteration of GABAergic Input Precedes Neurodegeneration of Cerebellar Purkinje Cells of NPC1-Deficient Mice

Rabenstein

Murr

Hermann

et al. 2019

IJMS

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Niemann-Pick Disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease belonging to the family of lysosomal storage disorders. NPC1-patients suffer from, amongst other symptoms, ataxia, based on the dysfunction and loss of cerebellar Purkinje cells. Alterations in synaptic transmission are believed to contribute to a pathological mechanism leading to the progressive loss of Purkinje cells observed in NPC1-deficient mice. With regard to inhibitory synaptic transmission, alterations of GABAergic synapses are described but functional data are missing. For this reason, we have examined here the inhibitory GABAergic synaptic transmission of Purkinje cells of NPC1-deficient mice (NPC1−/−). Patch clamp recordings of inhibitory post-synaptic currents (IPSCs) of Purkinje cells revealed an increased frequency of GABAergic IPSCs in NPC1−/− mice. In addition, Purkinje cells of NPC1−/− mice were less amenable for modulation of synaptic transmission via the activation of excitatory NMDA-receptors (NMDA-Rs). Western blot testing disclosed a reduced protein level of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) subunit GluA2 in the cerebella of NPC1−/− mice, indicating a disturbance in the internalization of GluA2-containing AMPA-Rs. Since this is triggered by the activation of NMDA-Rs, we conclude that a disturbance in the synaptic turnover of AMPA-Rs underlies the defective inhibitory GABAergic synaptic transmission. While these alterations precede obvious signs of neurodegeneration of Purkinje cells, we propose a contribution of synaptic malfunction to the initiation of the loss of Purkinje cells in NPC1. Thus, a prevention of the disturbance of synaptic transmission in early stages of the disease might display a target with which to avert progressive neurodegeneration in NPC1.

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NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

Cited by 47 publications

References 55 publications

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

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

CYP46A1-dependent and independent effects of efavirenz treatment

Alteration of GABAergic Input Precedes Neurodegeneration of Cerebellar Purkinje Cells of NPC1-Deficient Mice

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