학술논문
Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development
Document Type
article
Author
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; Sotirios Ntikas; Christos S. Bartsocas; Margarita Markouri; Eleni Antoniadou; Ioanna Laina; Owain W. Howell; Meng Li; Yuqin Wang; William J. Griffiths; Emma L. Lane; Mariah J. Lelos; Spyridon Theofilopoulos
Source
iScience, Vol 27, Iss 1, Pp 108670- (2024)
Subject
Language
English
ISSN
2589-0042
Abstract
Summary: 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 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.