iScience (Jan 2024)

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

Journal volume & issue
Vol. 27, no. 1
p. 108670

Abstract

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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.

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