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24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo

Spyridon Theofilopoulos Orcid Logo, Willy Antoni Abreu de Oliveira, Shanzheng Yang, Eylan Yutuc Orcid Logo, Ahmed Saeed, Jonas Abdel-Khalik, Abbe Ullgren, Angel Cedazo-Minguez, Ingemar Björkhem, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Ernest Arenas

Journal of Biological Chemistry, Volume: 294, Issue: 11, Pages: 4169 - 4176

Swansea University Authors: Spyridon Theofilopoulos Orcid Logo, Eylan Yutuc Orcid Logo, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo

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DOI (Published version): 10.1074/jbc.ra118.005639

Abstract

The liver X receptors Lxrα/NR1H3 and Lxrβ/NR1H2 are ligand-dependent nuclear receptors critical for midbrain dopaminergic (mDA) neuron development. We previously found that 24(S),25-epoxycholesterol (24,25-EC), the most potent and abundant Lxr ligand in the developing mouse midbrain, promotes mDA ne...

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Published in: Journal of Biological Chemistry
ISSN: 0021-9258 1083-351X
Published: Elsevier BV 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa48277
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We previously found that 24(S),25-epoxycholesterol (24,25-EC), the most potent and abundant Lxr ligand in the developing mouse midbrain, promotes mDA neurogenesis in vitro. In this study, we demonstrate that 24,25-EC promotes mDA neurogenesis in an Lxr-dependent manner, in the developing mouse midbrain in vivo and also prevents toxicity induced by the Lxr inhibitor geranylgeranyl pyrophosphate. Furthermore, using MS we show that overexpression of human cholesterol 24S-hydroxylase (CYP46A1) increases the levels of both 24(S)-hydroxycholesterol (24-HC) and 24,25-EC in the developing midbrain, resulting in a specific increase in mDA neurogenesis in vitro and in vivo, but has no effect on occulomotor or red nucleus neurogenesis. 24-HC, unlike 24,25-EC, did not affect in vitro neurogenesis, indicating that the neurogenic effect of 24,25-EC on mDA neurons is specific. Combined, our results indicate that increased levels of 24,25-EC in vivo, by intracerebroventricular delivery in wild-type mice or by overexpression of its biosynthetic enzyme CYP46A1, specifically promote mDA neurogenesis. We propose that increasing the levels of 24,25-EC in vivo may be a useful strategy to combat the loss of mDA neurons in Parkinson&#x2019;s disease.</abstract><type>Journal Article</type><journal>Journal of Biological Chemistry</journal><volume>294</volume><journalNumber>11</journalNumber><paginationStart>4169</paginationStart><paginationEnd>4176</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0021-9258</issnPrint><issnElectronic>1083-351X</issnElectronic><keywords>CYP46A1, dopamine neuron, Liver X Receptor, midbrain, oxysterol, mass spectrometry (MS), neurogenesis, lipid metabolism, development, neurodegenerative disease</keywords><publishedDay>15</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-03-15</publishedDate><doi>10.1074/jbc.ra118.005639</doi><url>http://dx.doi.org/10.1074/jbc.ra118.005639</url><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders/><projectreference/><lastEdited>2023-02-14T16:30:44.0879714</lastEdited><Created>2019-01-18T07:09:34.3145235</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Spyridon</firstname><surname>Theofilopoulos</surname><orcid>0000-0003-1986-0943</orcid><order>1</order></author><author><firstname>Willy Antoni Abreu de</firstname><surname>Oliveira</surname><order>2</order></author><author><firstname>Shanzheng</firstname><surname>Yang</surname><order>3</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>4</order></author><author><firstname>Ahmed</firstname><surname>Saeed</surname><order>5</order></author><author><firstname>Jonas</firstname><surname>Abdel-Khalik</surname><order>6</order></author><author><firstname>Abbe</firstname><surname>Ullgren</surname><order>7</order></author><author><firstname>Angel</firstname><surname>Cedazo-Minguez</surname><order>8</order></author><author><firstname>Ingemar</firstname><surname>Bj&#xF6;rkhem</surname><order>9</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>10</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>11</order></author><author><firstname>Ernest</firstname><surname>Arenas</surname><order>12</order></author></authors><documents><document><filename>48277__13262__40609d2aff674f8cba5c077c9cb42582.pdf</filename><originalFilename>48277.pdf</originalFilename><uploaded>2019-03-26T15:32:08.9330000</uploaded><type>Output</type><contentLength>2286308</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><embargoDate>2019-03-25T00:00:00.0000000</embargoDate><documentNotes>Released under the terms of a Creative Commons Attribution License (CC-BY).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2023-02-14T16:30:44.0879714 v2 48277 2019-01-18 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo bcd1bdbdf59d0724d2f9e9a48e671107 0000-0003-1986-0943 Spyridon Theofilopoulos Spyridon Theofilopoulos true false 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2019-01-18 MEDS The liver X receptors Lxrα/NR1H3 and Lxrβ/NR1H2 are ligand-dependent nuclear receptors critical for midbrain dopaminergic (mDA) neuron development. We previously found that 24(S),25-epoxycholesterol (24,25-EC), the most potent and abundant Lxr ligand in the developing mouse midbrain, promotes mDA neurogenesis in vitro. In this study, we demonstrate that 24,25-EC promotes mDA neurogenesis in an Lxr-dependent manner, in the developing mouse midbrain in vivo and also prevents toxicity induced by the Lxr inhibitor geranylgeranyl pyrophosphate. Furthermore, using MS we show that overexpression of human cholesterol 24S-hydroxylase (CYP46A1) increases the levels of both 24(S)-hydroxycholesterol (24-HC) and 24,25-EC in the developing midbrain, resulting in a specific increase in mDA neurogenesis in vitro and in vivo, but has no effect on occulomotor or red nucleus neurogenesis. 24-HC, unlike 24,25-EC, did not affect in vitro neurogenesis, indicating that the neurogenic effect of 24,25-EC on mDA neurons is specific. Combined, our results indicate that increased levels of 24,25-EC in vivo, by intracerebroventricular delivery in wild-type mice or by overexpression of its biosynthetic enzyme CYP46A1, specifically promote mDA neurogenesis. We propose that increasing the levels of 24,25-EC in vivo may be a useful strategy to combat the loss of mDA neurons in Parkinson’s disease. Journal Article Journal of Biological Chemistry 294 11 4169 4176 Elsevier BV 0021-9258 1083-351X CYP46A1, dopamine neuron, Liver X Receptor, midbrain, oxysterol, mass spectrometry (MS), neurogenesis, lipid metabolism, development, neurodegenerative disease 15 3 2019 2019-03-15 10.1074/jbc.ra118.005639 http://dx.doi.org/10.1074/jbc.ra118.005639 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2023-02-14T16:30:44.0879714 2019-01-18T07:09:34.3145235 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Spyridon Theofilopoulos 0000-0003-1986-0943 1 Willy Antoni Abreu de Oliveira 2 Shanzheng Yang 3 Eylan Yutuc 0000-0001-9971-1950 4 Ahmed Saeed 5 Jonas Abdel-Khalik 6 Abbe Ullgren 7 Angel Cedazo-Minguez 8 Ingemar Björkhem 9 Yuqin Wang 0000-0002-3063-3066 10 William Griffiths 0000-0002-4129-6616 11 Ernest Arenas 12 48277__13262__40609d2aff674f8cba5c077c9cb42582.pdf 48277.pdf 2019-03-26T15:32:08.9330000 Output 2286308 application/pdf Version of Record true 2019-03-25T00:00:00.0000000 Released under the terms of a Creative Commons Attribution License (CC-BY). true eng
title 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
spellingShingle 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
Spyridon Theofilopoulos
Eylan Yutuc
Yuqin Wang
William Griffiths
title_short 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
title_full 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
title_fullStr 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
title_full_unstemmed 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
title_sort 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo
author_id_str_mv bcd1bdbdf59d0724d2f9e9a48e671107
99332f073ce913a9b7d8b6441b17516d
c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv bcd1bdbdf59d0724d2f9e9a48e671107_***_Spyridon Theofilopoulos
99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author Spyridon Theofilopoulos
Eylan Yutuc
Yuqin Wang
William Griffiths
author2 Spyridon Theofilopoulos
Willy Antoni Abreu de Oliveira
Shanzheng Yang
Eylan Yutuc
Ahmed Saeed
Jonas Abdel-Khalik
Abbe Ullgren
Angel Cedazo-Minguez
Ingemar Björkhem
Yuqin Wang
William Griffiths
Ernest Arenas
format Journal article
container_title Journal of Biological Chemistry
container_volume 294
container_issue 11
container_start_page 4169
publishDate 2019
institution Swansea University
issn 0021-9258
1083-351X
doi_str_mv 10.1074/jbc.ra118.005639
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1074/jbc.ra118.005639
document_store_str 1
active_str 0
description The liver X receptors Lxrα/NR1H3 and Lxrβ/NR1H2 are ligand-dependent nuclear receptors critical for midbrain dopaminergic (mDA) neuron development. We previously found that 24(S),25-epoxycholesterol (24,25-EC), the most potent and abundant Lxr ligand in the developing mouse midbrain, promotes mDA neurogenesis in vitro. In this study, we demonstrate that 24,25-EC promotes mDA neurogenesis in an Lxr-dependent manner, in the developing mouse midbrain in vivo and also prevents toxicity induced by the Lxr inhibitor geranylgeranyl pyrophosphate. Furthermore, using MS we show that overexpression of human cholesterol 24S-hydroxylase (CYP46A1) increases the levels of both 24(S)-hydroxycholesterol (24-HC) and 24,25-EC in the developing midbrain, resulting in a specific increase in mDA neurogenesis in vitro and in vivo, but has no effect on occulomotor or red nucleus neurogenesis. 24-HC, unlike 24,25-EC, did not affect in vitro neurogenesis, indicating that the neurogenic effect of 24,25-EC on mDA neurons is specific. Combined, our results indicate that increased levels of 24,25-EC in vivo, by intracerebroventricular delivery in wild-type mice or by overexpression of its biosynthetic enzyme CYP46A1, specifically promote mDA neurogenesis. We propose that increasing the levels of 24,25-EC in vivo may be a useful strategy to combat the loss of mDA neurons in Parkinson’s disease.
published_date 2019-03-15T04:42:15Z
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