U18666A, an activator of sterol regulatory element binding protein pathway, modulates presynaptic dopaminergic phenotype of SH-SY5Y neuroblastoma cells.
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.
['Schmitt|Mathieu|M|', 'Dehay|Benjamin|B|', 'Bezard|Erwan|E|0000-0002-0410-4638', 'Garcia-Ladona|F Javier|FJ|']
D021581:Active Transport, Cell Nucleus D000736:Androstenes D000924:Anticholesteremic Agents D045744:Cell Line, Tumor D002467:Cell Nucleus D015259:Dopamine Agents D059290:Dopaminergic Neurons D015870:Gene Expression D006801:Humans D008562:Membrane Glycoproteins D009419:Nerve Tissue Proteins D017729:Presynaptic Terminals D011759:Pyrrolidines D012333:RNA, Messenger D015398:Signal Transduction D051779:Sterol Regulatory Element Binding Proteins D062805:Synaptogyrins D050493:Vesicular Monoamine Transport Proteins
statins Parkinson's disease SREBP PF-429242 dopamine S1P cholesterol neurodifferentiation nuclear translocation