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Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development
James Hennegan,
Aled H. Bryant,
Lauren Griffiths,
Matthieu Trigano,
Oliver J.M. Bartley,
Joanna J. Bartlett,
Carys Minahan,
Willy Antoni Abreu de Oliveira,
Eylan Yutuc 
,
Sotiris Ntikas,
Christos S. Bartsocas,
Margarita Markouri,
Eleni Antoniadou,
Ioanna Laina,
Owain Howell ,
Meng Li,
Yuqin Wang ,
William Griffiths ,
Emma L. Lane,
Mariah J. Lelos,
Spyridon Theofilopoulos
,
Sotiris Ntikas,
Christos S. Bartsocas,
Margarita Markouri,
Eleni Antoniadou,
Ioanna Laina,
Owain Howell ,
Meng Li,
Yuqin Wang ,
William Griffiths ,
Emma L. Lane,
Mariah J. Lelos,
Spyridon Theofilopoulos
iScience, Volume: 27, Issue: 1, Start page: 108670
Swansea University Authors:
James Hennegan, Lauren Griffiths, Eylan Yutuc , Sotiris Ntikas, Owain Howell , Yuqin Wang , William Griffiths , Spyridon Theofilopoulos
DOI (Published version): 10.1016/j.isci.2023.108670
Abstract
Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), also known as 7α,27-dihydroxycholesterol, was significantly elevated in the cerebrospinal fluid (CSF) of Parkinson's disease pat...
| Published in: | iScience |
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| ISSN: | 2589-0042 |
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Elsevier BV
2024
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<?xml version="1.0" encoding="utf-8"?><rfc1807 xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xsd="http://www.w3.org/2001/XMLSchema"><bib-version>v2</bib-version><id>65068</id><entry>2023-11-22</entry><title>Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development</title><swanseaauthors><author><sid>588979cf96da5319b22932ae46c954ae</sid><firstname>James</firstname><surname>Hennegan</surname><name>James Hennegan</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>0ba2d38e7ebf13718fe6b1477fb7241c</sid><firstname>Lauren</firstname><surname>Griffiths</surname><name>Lauren Griffiths</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>99332f073ce913a9b7d8b6441b17516d</sid><ORCID>0000-0001-9971-1950</ORCID><firstname>Eylan</firstname><surname>Yutuc</surname><name>Eylan Yutuc</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>9376965a3aeaceac5205630d6eff9909</sid><firstname>Sotiris</firstname><surname>Ntikas</surname><name>Sotiris Ntikas</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>58c995486fc93a242b987640b692db8c</sid><ORCID>0000-0003-2157-9157</ORCID><firstname>Owain</firstname><surname>Howell</surname><name>Owain Howell</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>c92729b58622f9fdf6a0e7d8f4ce5081</sid><ORCID>0000-0002-3063-3066</ORCID><firstname>Yuqin</firstname><surname>Wang</surname><name>Yuqin Wang</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>3316b1d1b524be1831790933eed1c26e</sid><ORCID>0000-0002-4129-6616</ORCID><firstname>William</firstname><surname>Griffiths</surname><name>William Griffiths</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>bcd1bdbdf59d0724d2f9e9a48e671107</sid><ORCID>0000-0003-1986-0943</ORCID><firstname>Spyridon</firstname><surname>Theofilopoulos</surname><name>Spyridon Theofilopoulos</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2023-11-22</date><deptcode>BMS</deptcode><abstract>Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), also known as 7α,27-dihydroxycholesterol, was significantly elevated in the cerebrospinal fluid (CSF) of Parkinson's disease patients. In this study we investigated the role of 7α,26-diHC in mouse and human midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis in mouse midbrain progenitor cultures and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, but not the non-azole inhibitor metyrapone, increases the number of mDA neurons. Moreover, voriconazole prevents the loss of mDA neurons induced by 7α,26-diHC in hESC-derived cultures and in mouse progenitor cultures. These effects on mDA neurons are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons in human and mouse midbrain progenitor cultures. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol (24,25-EC), which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. The findings presented in this study suggest that voriconazole, and/or other azole CYP7B1 inhibitors, could be utilised as protective agents for mDA neurons and may have implications for Parkinson's disease therapy development.</abstract><type>Journal Article</type><journal>iScience</journal><volume>27</volume><journalNumber>1</journalNumber><paginationStart>108670</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2589-0042</issnPrint><issnElectronic/><keywords/><publishedDay>19</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-01-19</publishedDate><doi>10.1016/j.isci.2023.108670</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><funders>BB/N015932/1, BB/S019588/1, BB/L001942/1</funders><projectreference>BB/N015932/1, BB/S019588/1, BB/L001942/1</projectreference><lastEdited>2024-04-16T12:47:47.2704029</lastEdited><Created>2023-11-22T10:30:37.8388130</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>James</firstname><surname>Hennegan</surname><order>1</order></author><author><firstname>Aled H.</firstname><surname>Bryant</surname><order>2</order></author><author><firstname>Lauren</firstname><surname>Griffiths</surname><order>3</order></author><author><firstname>Matthieu</firstname><surname>Trigano</surname><order>4</order></author><author><firstname>Oliver J.M.</firstname><surname>Bartley</surname><order>5</order></author><author><firstname>Joanna J.</firstname><surname>Bartlett</surname><order>6</order></author><author><firstname>Carys</firstname><surname>Minahan</surname><order>7</order></author><author><firstname>Willy Antoni Abreu de</firstname><surname>Oliveira</surname><order>8</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>9</order></author><author><firstname>Sotiris</firstname><surname>Ntikas</surname><order>10</order></author><author><firstname>Christos S.</firstname><surname>Bartsocas</surname><order>11</order></author><author><firstname>Margarita</firstname><surname>Markouri</surname><order>12</order></author><author><firstname>Eleni</firstname><surname>Antoniadou</surname><order>13</order></author><author><firstname>Ioanna</firstname><surname>Laina</surname><order>14</order></author><author><firstname>Owain</firstname><surname>Howell</surname><orcid>0000-0003-2157-9157</orcid><order>15</order></author><author><firstname>Meng</firstname><surname>Li</surname><order>16</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>17</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>18</order></author><author><firstname>Emma L.</firstname><surname>Lane</surname><order>19</order></author><author><firstname>Mariah J.</firstname><surname>Lelos</surname><order>20</order></author><author><firstname>Spyridon</firstname><surname>Theofilopoulos</surname><orcid>0000-0003-1986-0943</orcid><order>21</order></author></authors><documents><document><filename>65068__29298__b423692a964c46bd8a881c41d52e08c7.pdf</filename><originalFilename>PUBLISHED_PIIS2589004223027475.pdf</originalFilename><uploaded>2023-12-20T08:42:20.0425590</uploaded><type>Output</type><contentLength>5440264</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>This is an open access article under the CC BY license.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807> |
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v2 65068 2023-11-22 Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development 588979cf96da5319b22932ae46c954ae James Hennegan James Hennegan true false 0ba2d38e7ebf13718fe6b1477fb7241c Lauren Griffiths Lauren Griffiths true false 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false 9376965a3aeaceac5205630d6eff9909 Sotiris Ntikas Sotiris Ntikas true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false bcd1bdbdf59d0724d2f9e9a48e671107 0000-0003-1986-0943 Spyridon Theofilopoulos Spyridon Theofilopoulos true false 2023-11-22 BMS Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), also known as 7α,27-dihydroxycholesterol, was significantly elevated in the cerebrospinal fluid (CSF) of Parkinson's disease patients. In this study we investigated the role of 7α,26-diHC in mouse and human midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis in mouse midbrain progenitor cultures and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, but not the non-azole inhibitor metyrapone, increases the number of mDA neurons. Moreover, voriconazole prevents the loss of mDA neurons induced by 7α,26-diHC in hESC-derived cultures and in mouse progenitor cultures. These effects on mDA neurons are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons in human and mouse midbrain progenitor cultures. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol (24,25-EC), which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. The findings presented in this study suggest that voriconazole, and/or other azole CYP7B1 inhibitors, could be utilised as protective agents for mDA neurons and may have implications for Parkinson's disease therapy development. Journal Article iScience 27 1 108670 Elsevier BV 2589-0042 19 1 2024 2024-01-19 10.1016/j.isci.2023.108670 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) BB/N015932/1, BB/S019588/1, BB/L001942/1 BB/N015932/1, BB/S019588/1, BB/L001942/1 2024-04-16T12:47:47.2704029 2023-11-22T10:30:37.8388130 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science James Hennegan 1 Aled H. Bryant 2 Lauren Griffiths 3 Matthieu Trigano 4 Oliver J.M. Bartley 5 Joanna J. Bartlett 6 Carys Minahan 7 Willy Antoni Abreu de Oliveira 8 Eylan Yutuc 0000-0001-9971-1950 9 Sotiris Ntikas 10 Christos S. Bartsocas 11 Margarita Markouri 12 Eleni Antoniadou 13 Ioanna Laina 14 Owain Howell 0000-0003-2157-9157 15 Meng Li 16 Yuqin Wang 0000-0002-3063-3066 17 William Griffiths 0000-0002-4129-6616 18 Emma L. Lane 19 Mariah J. Lelos 20 Spyridon Theofilopoulos 0000-0003-1986-0943 21 65068__29298__b423692a964c46bd8a881c41d52e08c7.pdf PUBLISHED_PIIS2589004223027475.pdf 2023-12-20T08:42:20.0425590 Output 5440264 application/pdf Version of Record true This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/ |
| title |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| spellingShingle |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development James Hennegan Lauren Griffiths Eylan Yutuc Sotiris Ntikas Owain Howell Yuqin Wang William Griffiths Spyridon Theofilopoulos |
| title_short |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_full |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_fullStr |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_full_unstemmed |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_sort |
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| author_id_str_mv |
588979cf96da5319b22932ae46c954ae 0ba2d38e7ebf13718fe6b1477fb7241c 99332f073ce913a9b7d8b6441b17516d 9376965a3aeaceac5205630d6eff9909 58c995486fc93a242b987640b692db8c c92729b58622f9fdf6a0e7d8f4ce5081 3316b1d1b524be1831790933eed1c26e bcd1bdbdf59d0724d2f9e9a48e671107 |
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588979cf96da5319b22932ae46c954ae_***_James Hennegan 0ba2d38e7ebf13718fe6b1477fb7241c_***_Lauren Griffiths 99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc 9376965a3aeaceac5205630d6eff9909_***_Sotiris Ntikas 58c995486fc93a242b987640b692db8c_***_Owain Howell c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang 3316b1d1b524be1831790933eed1c26e_***_William Griffiths bcd1bdbdf59d0724d2f9e9a48e671107_***_Spyridon Theofilopoulos |
| author |
James Hennegan Lauren Griffiths Eylan Yutuc Sotiris Ntikas Owain Howell Yuqin Wang William Griffiths Spyridon Theofilopoulos |
| author2 |
James Hennegan Aled H. Bryant Lauren Griffiths Matthieu Trigano Oliver J.M. Bartley Joanna J. Bartlett Carys Minahan Willy Antoni Abreu de Oliveira Eylan Yutuc Sotiris Ntikas Christos S. Bartsocas Margarita Markouri Eleni Antoniadou Ioanna Laina Owain Howell Meng Li Yuqin Wang William Griffiths Emma L. Lane Mariah J. Lelos Spyridon Theofilopoulos |
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iScience |
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27 |
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108670 |
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2024 |
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Swansea University |
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2589-0042 |
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10.1016/j.isci.2023.108670 |
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Elsevier BV |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
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Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), also known as 7α,27-dihydroxycholesterol, was significantly elevated in the cerebrospinal fluid (CSF) of Parkinson's disease patients. In this study we investigated the role of 7α,26-diHC in mouse and human midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis in mouse midbrain progenitor cultures and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, but not the non-azole inhibitor metyrapone, increases the number of mDA neurons. Moreover, voriconazole prevents the loss of mDA neurons induced by 7α,26-diHC in hESC-derived cultures and in mouse progenitor cultures. These effects on mDA neurons are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons in human and mouse midbrain progenitor cultures. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol (24,25-EC), which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. The findings presented in this study suggest that voriconazole, and/or other azole CYP7B1 inhibitors, could be utilised as protective agents for mDA neurons and may have implications for Parkinson's disease therapy development. |
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2024-01-19T12:47:44Z |
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11.013148 |