Retracted: Differential effects of 24‐hydroxycholesterol and 27‐hydroxycholesterol on tyrosine hydroxylase and α‐synuclein in human neuroblastoma SH‐SY5Y cells

Abstract

Loss of dopaminergic neurons and α-synuclein accumulation are the two major pathological hallmarks of Parkinson’s disease (PD). 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. Here, 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 ECHS 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 PD by precluding TH reduction and α-synuclein accumulation.

Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis

“…Indeed, 7-ketocholesterol and 7b-hydroxycholesterol are found at high levels in atherosclerotic plaques (Garcia-Cruset et al, 1999, in the plasma of patients with cardiovascular diseases (Zieden et al, 1999;Zhou et al, 2000), and in the plasma of subjects tested after a fat-rich meal (Emanuel et al, 1991). In addition to atherosclerosis, it is now suggested that oxysterols could also contribute to the development of other important diseases including neurodegenerative diseases such as Alzheimer's disease (Björkhem, 2006;Cao et al, 2007;Vaya and Schipper, 2007), Parkinson's disease (Bosco et al 2006;Rantham Prabhakara et al, 2008), and multiple sclerosis (Diestel et al, 2003;Leoni et al, 2005), as well as age-related diseases such as age-related macular degeneration (Malvitte et al, 2006) and cataract (Girao et al, 1998) (Table 1). In these diseases, inflammation is a major driving force, and it has been suggested that the oxidation of cholesterol in oxysterols could be a crucial step for the development of cellular stress and tissue damage leading to the initiation and development of these pathologies (Leonarduzzi et al, 2008).…”

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

“…Oxidized cholesterol derivatives, which are essentially aldehydes, are toxic substances that speed up the aggregation of S ␣ and perpetuate the cycle of degeneration [78] . Moreover, a recent study reported that 27-OH-cholesterol reduces tyrosine hydroxylase and increases ␣ -synuclein expression in neuronal cell cultures [79] . Statins were shown to reduce ␣ -synuclein aggregation in an in vitro model of PD [80] .…”

Lipid Metabolism in Neurodegenerative Diseases

“…More intriguingly, the monomeric form of all three peptides, mHTT, Ab, and a-synuclein, is intrinsically unstructured, whereby the secondary structures are unlikely to spontaneously fold into well-organized globular structures [17]. In the case of both Ab and a-synuclein, the influence of different types of lipids has been shown to accelerate or stabilize the formation of fibrils like betasheets [18][19][20][21][22][23][24][25].…”