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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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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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Published in: iScience
ISSN: 2589-0042
Published: Elsevier BV 2024
Online Access: Check full text

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.
College: Faculty of Medicine, Health and Life Sciences
Funders: BB/N015932/1, BB/S019588/1, BB/L001942/1
Issue: 1
Start Page: 108670