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

摘要

Loss of dopaminergic neurons and alpha-synuclein accumulation are the two major pathological hallmarks of Parkinson's disease. Currently, the mechanisms governing depletion of dopamine content and alpha-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 alpha-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 alpha-synuclein expression levels through the estrogen receptors (ER) and liver X receptors (LXR). We specifically show that inhibition of ERbeta 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 alpha-synuclein while the LXR antagonist 5alpha-6alpha-epoxycholesterol-3-sulfate significantly attenuated the 27-OHC-induced increase in alpha-synuclein expression. We further demonstrate that LXRbeta positively regulates alpha-synuclein expression and 27-OHC increases LXRbeta-mediated alpha-synuclein transcription. Our results demonstrate the involvement of two distinct pathways that are involved in the 27-OHC regulation of TH and alpha-synuclein levels. Concomitant activation of ERbeta and inhibition of LXRbeta prevent 27-OHC effects and may therefore reduce the progression of Parkinson's disease by precluding TH reduction and alpha-synuclein accumulation.