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.
J Neurochem
; 119(5): 1119-36, 2011 Dec.
Article
em En
| MEDLINE
| ID: mdl-21951066
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 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 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 LXRß positively regulates α-synuclein expression and 27-OHC increases LXRß-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 ERß and inhibition of LXRß prevent 27-OHC effects and may therefore reduce the progression of Parkinson's disease by precluding TH reduction and α-synuclein accumulation.
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Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Tirosina 3-Mono-Oxigenase
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Receptor alfa de Estrogênio
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Receptor beta de Estrogênio
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Alfa-Sinucleína
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Receptores Nucleares Órfãos
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Hidroxicolesteróis
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Neuroblastoma
Limite:
Humans
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos