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

Synapse. 2017 Sep;71(9). doi: 10.1002/syn.21980. Epub 2017 Jun 20.


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.

Keywords: PF-429242; Parkinson's disease; S1P; SREBP; cholesterol; dopamine; neurodifferentiation; nuclear translocation; statins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Androstenes / pharmacology*
  • Anticholesteremic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Dopamine Agents / pharmacology*
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / physiology
  • Gene Expression / drug effects
  • Humans
  • Membrane Glycoproteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / physiology
  • Pyrrolidines / pharmacology
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Proteins / antagonists & inhibitors
  • Sterol Regulatory Element Binding Proteins / metabolism*
  • Synaptogyrins / metabolism
  • Vesicular Monoamine Transport Proteins / metabolism


  • Androstenes
  • Anticholesteremic Agents
  • Dopamine Agents
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • PF-429242
  • Pyrrolidines
  • RNA, Messenger
  • SLC18A2 protein, human
  • SV2C protein, human
  • SYNGR3 protein, human
  • Sterol Regulatory Element Binding Proteins
  • Synaptogyrins
  • Vesicular Monoamine Transport Proteins
  • SV2A protein, human
  • 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one