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; 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

doi:10.1016/j.isci.2023.108670

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

iScience. 2023 Dec 7;27(1):108670. doi: 10.1016/j.isci.2023.108670. eCollection 2024 Jan 19.

Authors

James Hennegan^{1

2}, Aled H Bryant¹, Lauren Griffiths^{1

3

4}, Matthieu Trigano⁵, Oliver J M Bartley², Joanna J Bartlett¹, Carys Minahan⁶, Willy Antoni Abreu de Oliveira⁷, Eylan Yutuc³, Sotirios Ntikas¹, Christos S Bartsocas⁸, Margarita Markouri⁸, Eleni Antoniadou⁸, Ioanna Laina⁸, Owain W Howell⁴, Meng Li^{5

9}, Yuqin Wang³, William J Griffiths³, Emma L Lane^{6

10}, Mariah J Lelos², Spyridon Theofilopoulos¹

Affiliations

¹ Regenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UK.
² Brain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
³ Oxysterol Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK.
⁴ Multiple Sclerosis Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK.
⁵ Dementia Research Institute, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
⁶ School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK.
⁷ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
⁸ Athens Medical Center, 15125 Athens, Greece.
⁹ Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff CF24 4HQ, UK.
¹⁰ MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.

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 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.

Keywords: Biological sciences; Molecular neuroscience; neuroscience.

Abstract

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