U18666A, an Activator of Sterol Regulatory Element Binding Protein (SREBP) Pathway Modulates Presynaptic Dopaminergic Phenotype of SH-SY5Y Neuroblastoma Cells.

Schmitt M(1)(2)(3), Dehay B(2)(3), Bezard E(2)(3), Garcia-Ladona FJ(1).

Author information:
(1)Neuroscience Therapeutic Area, New Medicines, UCB Biopharma SPRL, 1420 Braine
l’Alleud, Belgium.
(2)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
Bordeaux, 33000, France.
(3)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000,
France.

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.

© 2017 Wiley Periodicals, Inc.

DOI: 10.1002/syn.21980
PMID: 28407359 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus