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

Loss of dopaminergic neurons and a-synuclein accumulation are the two major pathological hallmarks of Parkinson’s disease (PD). Currently, the mechanisms governing depletion of dopamine content and a-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 a-synuclein levels in SH-SY5Y cells. However, the cellular mechanisms involved in 27-OHC effects were not elucidated. Here, we demonstrate that 27-OHC regulates TH and a-synuclein expression levels through the estrogen receptors (ER) and liver X receptors (LXR). We specifically show that inhibition of ERß 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 a-synuclein while the LXR antagonist ECHS significantly attenuated the 27-OHC-induced increase in a-synuclein expression. We further demonstrate that LXRß positively regulates a-synuclein expression and 27-OHC increases LXRß-mediated a-synuclein transcription. Our results demonstrate the involvement of two distinct pathways that are involved in the 27-OHC regulation of TH and a-synuclein levels. Concomitant activation of ERß and inhibition of LXRß prevent 27-OHC effects and may therefore reduce the progression of PD by precluding TH reduction and a-synuclein accumulation.