Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and alpha-synuclein in human neuroblastoma SH-SY5Y cells.
Evidence suggests that environmental and dietary factors may contribute to the pathogenesis of Parkinson's disease (PD). High dietary intake of cholesterol is such a factor that has been shown to increase or decrease the risk of PD. However, because circulating cholesterol does not cross the blood-brain barrier, the mechanisms linking dietary cholesterol to the pathogenesis of PD remain to be understood. In contrast to cholesterol, the oxidized cholesterol metabolites (oxysterols), 24S-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), can cross the blood-brain barrier and may place the brain at risk of degeneration. In this study, we incubated the human neuroblastoma SH-SY5Y cells for 24 h with 24-OHC, 27-OHC, or a mixture of 24-OHC plus 27-OHC, and have determined effects on tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis) levels, alpha-synuclein levels, and apoptosis. We demonstrate that while 24-OHC increases the levels of tyrosine hydroxylase, 27-OHC increases levels of alpha-synuclein, and induces apoptosis. Our findings show for the first time that oxysterols trigger changes in levels of proteins that are associated with the pathogenesis of PD. As steady state levels of 24-OHC and 27-OHC are tightly regulated in the brain, disturbances in these levels may contribute to the pathogenesis of PD.
Rantham Prabhakara
Jaya Prasanthi
JP
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
Feist
Gwen
G
Thomasson
Sarah
S
Thompson
Alex
A
Schommer
Eric
E
Ghribi
Othman
O
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D004338:Drug Combinations; D006888:Hydroxycholesterols; D013778:Tetrazolium Salts; D013844:Thiazoles; D051844:alpha-Synuclein; C044563:24-hydroxycholesterol; C076996:27-hydroxycholesterol; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; C022616:thiazolyl blue; D004298:Dopamine; D009638:Norepinephrine