title: 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.
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.
authors.affiliation: Department of Pharmacology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
authors.forename: Gurdeep
authors.initials: G
authors.lastname: Marwarha
authors.forename: Turk
authors.initials: T
authors.lastname: Rhen
authors.forename: Trevor
authors.initials: T
authors.lastname: Schommer
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C497604:SNCA protein, human; D051844:alpha-Synuclein; C076996:27-hydroxycholesterol; D014446:Tyrosine 3-Monooxygenase