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 investigat...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223027475 |
| _version_ | 1797383723331616768 |
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| 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 |
| author_facet | 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 |
| author_sort | James Hennegan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T21:25:31Z |
| format | Article |
| id | doaj.art-cc11eaec18cb42d988985f04f6f16725 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T21:25:31Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-cc11eaec18cb42d988985f04f6f167252023-12-21T07:36:20ZengElsevieriScience2589-00422024-01-01271108670Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron developmentJames Hennegan0Aled H. Bryant1Lauren Griffiths2Matthieu Trigano3Oliver J.M. Bartley4Joanna J. Bartlett5Carys Minahan6Willy Antoni Abreu de Oliveira7Eylan Yutuc8Sotirios Ntikas9Christos S. Bartsocas10Margarita Markouri11Eleni Antoniadou12Ioanna Laina13Owain W. Howell14Meng Li15Yuqin Wang16William J. Griffiths17Emma L. Lane18Mariah J. Lelos19Spyridon Theofilopoulos20Regenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UK; Brain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UKRegenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UKRegenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UK; Oxysterol Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK; Multiple Sclerosis Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UKDementia Research Institute, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UKBrain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UKRegenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UKSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UKLaboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, SwedenOxysterol Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UKRegenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UKAthens Medical Center, 15125 Athens, GreeceAthens Medical Center, 15125 Athens, GreeceAthens Medical Center, 15125 Athens, GreeceAthens Medical Center, 15125 Athens, GreeceMultiple Sclerosis Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UKDementia Research Institute, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff CF24 4HQ, UKOxysterol Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UKOxysterol Research Group, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UKSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UKBrain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UKRegenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223027475Biological sciencesneuroscienceMolecular neuroscience |
| spellingShingle | 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 Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development iScience Biological sciences neuroscience Molecular neuroscience |
| title | Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_full | Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_fullStr | Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_full_unstemmed | Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_short | Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| title_sort | inhibition of 7α 26 dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development |
| topic | Biological sciences neuroscience Molecular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223027475 |
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