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ORIGINAL ARTICLE
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
Article first published online: 24 OCT 2011
DOI: 10.1111/j.1471-4159.2011.07497.x
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Additional Information
How to Cite
Marwarha, G., Rhen, T., Schommer, T. and Ghribi, O. (2011), 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. Journal of Neurochemistry, 119: 1119–1136. doi: 10.1111/j.1471-4159.2011.07497.x
Publication History
- Issue published online: 14 NOV 2011
- Article first published online: 24 OCT 2011
- Accepted manuscript online: 23 SEP 2011 05:26AM EST
- Received June 6, 2011; revised manuscript received September 12, 2011; accepted September 19, 2011.
- Abstract
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Keywords:
- 27-hydroxycholesterol;
- α-synuclein;
- estrogen receptors;
- liver X receptor;
- Parkinson’s disease;
- tyrosine hydroxylase
J. Neurochem. (2011) 119, 1119–1136.
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.