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Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development
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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 |
| Published: |
Elsevier BV
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65068 |
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| 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. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
BB/N015932/1, BB/S019588/1, BB/L001942/1 |
| Issue: |
1 |
| Start Page: |
108670 |