Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development
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. © 2023 The Authors.
| Authors | Hennegan J, Bryant AH, Griffiths L, Trigano M, Bartley OJM, Bartlett JJ, Minahan C, Abreu de Oliveira WA, Yutuc E, Ntikas S, Bartsocas CS, Markouri M, Antoniadou E, Laina I, Howell OW, Li M, Wang Y, Griffiths WJ, Lane EL, Lelos MJ, Theofilopoulos S |
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| Journal | iScience |
| Publication Date | 2024 Jan 19;27(1):108670 |
| PubMed | 38155767 |
| PubMed Central | PMC10753067 |
| DOI | 10.1016/j.isci.2023.108670 |