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

Abstract

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), also known as 7α,27-dihydroxycholesterol, was significantly elevated in the cerebrospinal fluid (CSF) of Parkinson's disease patients. In this study we investigated the role of 7α,26-diHC in mouse and human midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis in mouse midbrain progenitor cultures and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, but not the non-azole inhibitor metyrapone, increases the number of mDA neurons. Moreover, voriconazole prevents the loss of mDA neurons induced by 7α,26-diHC in hESC-derived cultures and in mouse progenitor cultures. These effects on mDA neurons are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons in human and mouse midbrain progenitor cultures. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol (24,25-EC), which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. The findings presented in this study suggest that voriconazole, and/or other azole CYP7B1 inhibitors, could be utilised as protective agents for mDA neurons and may have implications for Parkinson's disease therapy development