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J Biol Chem. 2019 Mar 15;294(11):4169-4176. doi: 10.1074/jbc.RA118.005639. Epub 2019 Jan 17.

24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo.

Author information

1
From the Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden, s.theofilopoulos@swansea.ac.uk.
2
the Regenerative Neurobiology Laboratory, Swansea University Medical School, Institute of Life Science 1, Singleton Park, Swansea SA2 8PP, United Kingdom.
3
From the Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
4
the Institute of Life Science, Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, United Kingdom.
5
the Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm 14157, Sweden, and.
6
the Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm 14157, Sweden.
7
From the Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden, ernest.arenas@ki.se.

Abstract

The liver X receptors Lxrα/NR1H3 and Lxrβ/NR1H2 are ligand-dependent nuclear receptors critical for midbrain dopaminergic (mDA) neuron development. We found previously that 24(S),25-epoxycholesterol (24,25-EC), the most potent and abundant Lxr ligand in the developing mouse midbrain, promotes mDA neurogenesis in vitro In this study, we demonstrate that 24,25-EC promotes mDA neurogenesis in an Lxr-dependent manner in the developing mouse midbrain in vivo and also prevents toxicity induced by the Lxr inhibitor geranylgeranyl pyrophosphate. Furthermore, using MS, we show that overexpression of human cholesterol 24S-hydroxylase (CYP46A1) increases the levels of both 24(S)-hydroxycholesterol (24-HC) and 24,25-EC in the developing midbrain, resulting in a specific increase in mDA neurogenesis in vitro and in vivo, but has no effect on oculomotor or red nucleus neurogenesis. 24-HC, unlike 24,25-EC, did not affect in vitro neurogenesis, indicating that the neurogenic effect of 24,25-EC on mDA neurons is specific. Combined, our results indicate that increased levels of 24,25-EC in vivo, by intracerebroventricular delivery in WT mice or by overexpression of its biosynthetic enzyme CYP46A1, specifically promote mDA neurogenesis. We propose that increasing the levels of 24,25-EC in vivo may be a useful strategy to combat the loss of mDA neurons in Parkinson's disease.

KEYWORDS:

CYP46A1; MS; development; dopamine neuron; lipid metabolism; liver X receptor; midbrain; neurodegenerative disease; neurogenesis; oxysterol

PMID:
30655290
PMCID:
PMC6422085
DOI:
10.1074/jbc.RA118.005639
[Indexed for MEDLINE]
Free PMC Article

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