Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

James Hennegan; Aled Bryant; Lauren Griffiths; Matthieu Trigano; Oliver  Bartley; Joanna Bartlett; Carys Minahan; Willy Antoni Abreu de Oliveira; Eylan Yutuc; Sotirios Ntikas; Christos Bartsocas; Margarita Markouri; Eleni Antoniadou; Ioanna Laina; Owain Howell; Meng Li; Yuqin Wang; William Griffiths; Emma Lane; Mariah Lelos; Spyridon Theofilopoulos

doi:10.1016/j.isci.2023.108670

Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

James Hennegan, Aled Bryant, Lauren Griffiths, Matthieu Trigano, Oliver Bartley, Joanna Bartlett, Carys Minahan, Willy Antoni Abreu de Oliveira, Eylan Yutuc, Sotirios Ntikas, Christos Bartsocas, Margarita Markouri, Eleni Antoniadou, Ioanna Laina, Owain Howell, Meng Li, Yuqin Wang, William Griffiths, Emma Lane, Mariah LelosSpyridon Theofilopoulos^*

^*Corresponding author for this work

Faculty of Computing, Engineering and Science

Research output: Contribution to journal › Article › peer-review

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Abstract

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25 R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1 + oculomotor neurons. Furthermore, our results suggest that elevated 24( S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development.

Original language	English
Article number	108670
Number of pages	15
Journal	iScience
Volume	27
Issue number	1
Early online date	6 Dec 2023
DOIs	https://doi.org/10.1016/j.isci.2023.108670
Publication status	Published - 19 Jan 2024

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Hennegan, J., Bryant, A., Griffiths, L., Trigano, M., Bartley, O., Bartlett, J., Minahan, C., de Oliveira, W. A. A., Yutuc, E., Ntikas, S., Bartsocas, C., Markouri, M., Antoniadou, E., Laina, I., Howell, O., Li, M., Wang, Y., Griffiths, W., Lane, E., ... Theofilopoulos, S. (2024). Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development. iScience, 27(1), Article 108670. https://doi.org/10.1016/j.isci.2023.108670

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title = "Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.",

abstract = "Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25 R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1 + oculomotor neurons. Furthermore, our results suggest that elevated 24( S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development. ",

author = "James Hennegan and Aled Bryant and Lauren Griffiths and Matthieu Trigano and Oliver Bartley and Joanna Bartlett and Carys Minahan and {de Oliveira}, {Willy Antoni Abreu} and Eylan Yutuc and Sotirios Ntikas and Christos Bartsocas and Margarita Markouri and Eleni Antoniadou and Ioanna Laina and Owain Howell and Meng Li and Yuqin Wang and William Griffiths and Emma Lane and Mariah Lelos and Spyridon Theofilopoulos",

year = "2024",

month = jan,

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doi = "10.1016/j.isci.2023.108670",

language = "English",

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Hennegan, J, Bryant, A, Griffiths, L, Trigano, M, Bartley, O, Bartlett, J, Minahan, C, de Oliveira, WAA, Yutuc, E, Ntikas, S, Bartsocas, C, Markouri, M, Antoniadou, E, Laina, I, Howell, O, Li, M, Wang, Y, Griffiths, W, Lane, E, Lelos, M & Theofilopoulos, S 2024, 'Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.', iScience, vol. 27, no. 1, 108670. https://doi.org/10.1016/j.isci.2023.108670

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T1 - Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

AU - Hennegan, James

AU - Bryant, Aled

AU - Griffiths, Lauren

AU - Trigano, Matthieu

AU - Bartley, Oliver

AU - Bartlett, Joanna

AU - Minahan, Carys

AU - de Oliveira, Willy Antoni Abreu

AU - Yutuc, Eylan

AU - Ntikas, Sotirios

AU - Bartsocas, Christos

AU - Markouri, Margarita

AU - Antoniadou, Eleni

AU - Laina, Ioanna

AU - Howell, Owain

AU - Li, Meng

AU - Wang, Yuqin

AU - Griffiths, William

AU - Lane, Emma

AU - Lelos, Mariah

AU - Theofilopoulos, Spyridon

PY - 2024/1/19

Y1 - 2024/1/19

N2 - Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25 R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1 + oculomotor neurons. Furthermore, our results suggest that elevated 24( S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development.

AB - Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25 R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1 + oculomotor neurons. Furthermore, our results suggest that elevated 24( S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development.

U2 - 10.1016/j.isci.2023.108670

DO - 10.1016/j.isci.2023.108670

M3 - Article

C2 - 38155767

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 1

M1 - 108670

ER -

Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

Abstract

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