Harnessing the trophic and modulatory potential of statins in a dopaminergic cell line.
Synapse. 2016-01-06; 70(3): 71-86
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1. Synapse. 2016 Mar;70(3):71-86. doi: 10.1002/syn.21881. Epub 2016 Jan 6.
Harnessing the trophic and modulatory potential of statins in a dopaminergic cell
Schmitt M(1)(2)(3), Dehay B(2)(3), Bezard E(2)(3), Garcia-Ladona FJ(1).
(1)Neuroscience Therapeutic Area, New Medicines, UCB Biopharma SPRL, 1420 Braine
(2)University De Bordeaux, Institut Des Maladies Neurodégénératives, UMR 5293,
Bordeaux, 33000, France.
(3)CNRS, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000,
The identification of an effective disease-modifying treatment for the
neurodegenerative progression in Parkinson’s disease (PD) remains a major
challenge. Epidemiological studies have reported that intake of statins,
cholesterol lowering drugs, could be associated to a reduced risk of developing
PD. In-vivo studies suggest that statins may reduce the severity of dopaminergic
neurodegeneration. The trophic potential of statins and their impact on the
expression of dopaminergic synaptic markers and dopamine (DA) transport function
in SH-SY5Y cells has been investigated. The findings showed that statin treatment
induces neurite outgrowth involving a specific effect on the complexity of the
neurite branching pattern. Statins increased the levels of presynaptic
dopaminergic biomarkers such as vesicular monoamine transporter 2 (VMAT2),
synaptic vesicle glycoproteins 2A and 2C (SV2C), and synaptogyrin-3 (SYNGR3).
Gene expression analysis confirmed a rapid statin-induced up-regulation of
VMAT2-, SV2C-, and SYNGR3-mRNA levels. Assessment of [(3) H]DA transport in
statin-treated cells showed a reduction in DA uptake concomitant to a
modification of VMAT2 pharmacological properties. It was also observed that a
nuclear translocation of the sterol regulatory element-binding protein 1
(SREBP-1). The results suggested that statins induced phenotypic changes in
dopaminergic cells characterized by an increase of growth, complexity of
structural synaptic elements, and expression of key presynaptic proteins with
functional impact on the DA transport capacity. Statin-induced changes are likely
the result of a downstream modulation of SREBP-1 pathway. Overall, these
mechanisms may contribute to the neuroprotective or neurorestorative effects
observed in the dopaminergic system and strengthen the therapeutic potential of
statins for PD.
© 2016 Wiley Periodicals, Inc.
PMID: 26695835 [Indexed for MEDLINE]