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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 Orcid Logo, Sotiris Ntikas, Christos S. Bartsocas, Margarita Markouri, Eleni Antoniadou, Ioanna Laina, Owain Howell Orcid Logo, Meng Li, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Emma L. Lane, Mariah J. Lelos, Spyridon Theofilopoulos Orcid Logo

iScience, Volume: 27, Issue: 1, Start page: 108670

Swansea University Authors: James Hennegan, Lauren Griffiths, Eylan Yutuc Orcid Logo, Sotiris Ntikas, Owain Howell Orcid Logo, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Spyridon Theofilopoulos Orcid Logo

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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...

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ISSN: 2589-0042
Published: Elsevier BV 2024
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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. 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spelling 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 MEDS 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 Medical School COLLEGE CODE MEDS 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 2024-10-18T17:16:19.4618590 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
author_id_fullname_str_mv 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
format Journal article
container_title iScience
container_volume 27
container_issue 1
container_start_page 108670
publishDate 2024
institution Swansea University
issn 2589-0042
doi_str_mv 10.1016/j.isci.2023.108670
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
document_store_str 1
active_str 0
description 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.
published_date 2024-01-19T17:16:17Z
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score 11.037056

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