The oxysterol 27-hydroxycholesterol regulates α-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors-relevance to Parkinson's disease

Gurdeep Marwarha, Turk Rhen, Trevor Schommer, Othman Ghribi

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Loss of dopaminergic neurons and α-synuclein accumulation are the two major pathological hallmarks of Parkinson's disease. Currently, the mechanisms governing depletion of dopamine content and α-synuclein accumulation are not well understood. We showed that the oxysterol 27-hydroxycholesterol (27-OHC) reduces the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and increases α-synuclein levels in SH-SY5Y cells. However, the cellular mechanisms involved in 27-OHC effects were not elucidated. In this study, we demonstrate that 27-OHC regulates TH and α-synuclein expression levels through the estrogen receptors (ER) and liver X receptors (LXR). We specifically show that inhibition of ERβ mediates 27-OHC-induced decrease in TH expression, an effect reversed by the ER agonist estradiol. We also show that 27-OHC and the LXR agonist GW3965 increase α-synuclein while the LXR antagonist 5α-6α-epoxycholesterol-3-sulfate significantly attenuated the 27-OHC-induced increase in α-synuclein expression. We further demonstrate that LXRβ positively regulates α-synuclein expression and 27-OHC increases LXRβ-mediated α-synuclein transcription. Our results demonstrate the involvement of two distinct pathways that are involved in the 27-OHC regulation of TH and α-synuclein levels. Concomitant activation of ERβ and inhibition of LXRβ prevent 27-OHC effects and may therefore reduce the progression of Parkinson's disease by precluding TH reduction and α-synuclein accumulation.

Original languageEnglish (US)
Pages (from-to)1119-1136
Number of pages18
JournalJournal of Neurochemistry
Volume119
Issue number5
DOIs
StatePublished - Dec 2011

Keywords

  • 27-hydroxycholesterol
  • Parkinson's disease
  • estrogen receptors
  • liver X receptor
  • tyrosine hydroxylase
  • α-synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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