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

Hennegan, James, Bryant, Aled, Griffiths, Lauren, Trigano, Matthieu, Bartley, Oliver J. M., Bartlett, Joanna, Minahan, Carys, Abreu de Oliveira, Willy Antoni, Yutuc, Eylan, Ntikas, Sotiros, Bartsocas, Christos, Markouri, Margarita, Antoniadou, Eleni, Laina, Ioanna, Howell, Owain, Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643, Wang, Yuqin, Griffiths, William, Lane, Emma L. ORCID: https://orcid.org/0000-0001-8800-3764, Lelos, Mariah ORCID: https://orcid.org/0000-0001-7102-055X and Theofilopoulos, Spyridon 2024. Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development. iScience 27 (1) , 108670. 10.1016/j.isci.2023.108670

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Neuroscience and Mental Health Research Institute (NMHRI) Pharmacy Medicine Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Cell Press
ISSN:	2589-0042
Date of First Compliant Deposit:	6 December 2023
Date of Acceptance:	5 December 2023
Last Modified:	15 Jan 2024 15:37
URI:	https://orca.cardiff.ac.uk/id/eprint/164553

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