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

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7 alpha,(25R)26-dihydroxycholesterol (7 alpha,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7 alpha,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7 alpha,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7 alpha-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7 alpha,26-diHC. These effects are specific since neither 7 alpha,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.