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

Research output: Contribution to journalArticlepeer-review

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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), was significantly elevated in the cerebrospinal fluid of Parkinson's disease (PD) patients. 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 languageEnglish
Article number108670
Number of pages15
JournaliScience
Volume27
Issue number1
Early online date6 Dec 2023
DOIs
Publication statusPublished - 19 Jan 2024

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