U18666A, an activator of sterol regulatory element binding protein pathway, modulates presynaptic dopaminergic phenotype of SH-SY5Y neuroblastoma cells

Abstract

The therapeutic use of statins has been associated to a reduced risk of Parkinson's disease (PD) and may hold neuroprotective potential by counteracting the degeneration of dopaminergic neurons. Transcriptional activation of the sterol regulatory element-binding protein (SREBP) is one of the major downstream signaling pathways triggered by the cholesterol-lowering effect of statins. In a previous study in neuroblastoma cells, we have shown that statins consistently induce the upregulation of presynaptic dopaminergic proteins and changes of their function and these effects were accompanied by downstream activation of SREBP. In this study, we aimed to determine the direct role of SREBP pathway in the modulation of dopaminergic phenotype. We demonstrate that treatment of SH-SY5Y cells with U18666A, an SREBP activator, increases the translocation of SREBPs into the nucleus, increases the expression of SREBP-1, SREBP-2, and of the presynaptic dopaminergic markers such as vesicular monoamine transporter 2, synaptic vesicle glycoprotein 2 A and 2 C, synaptogyrin-3, and tyrosine hydroxylase. The addition of SREBP inhibitor, PF-429242, blocks the increase of U18666A-induced expression of SREBPs and presynaptic markers. Our results, in line with previously reported effects of statins, demonstrate that direct stimulation of SREBP translocation is associated to differentiation toward a dopaminergic-like phenotype and suggest that SREBP-mediated transcriptional activity may lead to the restoration of the presynaptic dopamine markers and may contribute to neuroprotection of dopaminergic neurons. These findings further support the potential protective role of statin in PD and shed light upon SREBP as a potential new target for developing disease-modifying treatment in PD.

The Role of Lipids in Parkinson’s Disease

“…Increased cholesterol reduces cell death [474] and modulates presynaptic DA phenotype by increasing TH and VMAT2 expression in SH-SY5Y cells [475] and enhancing ligand binding of DAT and VMAT2 in the brains from rats and monkeys [476]. However, hypercholesterolemia seems to cause DA neuronal loss and oxidative stress in the SN and the striatum, leading to motor impairment [477,478,479].…”

Knowledge graph analytics platform with LINCS and IDG for Parkinson’s disease target illumination

“…The high TIN-X rank (nds_rank=6 out of 103) indicates both novelty and importance (PD-relevance), as shown in figure 3a. Additionally, in figures 3b and 3c, two reference publications from the same authors, present experimental and theoretical evidence for connection between statin drugs, therapeutic effectiveness for PD, and the gene SYNGR3 (11,12). Figure 4 displays evidence paths connecting SYNGR3 with associated expression signatures and drugs, matched by our method.…”

New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment

“…In the context of dopaminergic system, it has been demonstrated that dopamine release is influenced by cholesterol levels [ 50 ]. Additionally, there is evidence to support the idea that both statins and activation of SREBP1 can increase the expression and enhance the function of presynaptic dopaminergic proteins [ 51 ].…”