title: Harnessing the trophic and modulatory potential of statins in a dopaminergic cell line.
abstract: 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.
authors.affiliation: Neuroscience Therapeutic Area, New Medicines, UCB Biopharma SPRL, 1420 Braine L'alleud, Belgium.|University De Bordeaux, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000, France.|CNRS, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: University De Bordeaux, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000, France.|CNRS, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.affiliation: University De Bordeaux, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000, France.|CNRS, Institut Des Maladies Neurodégénératives, UMR 5293, Bordeaux, 33000, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Neuroscience Therapeutic Area, New Medicines, UCB Biopharma SPRL, 1420 Braine L'alleud, Belgium.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Garcia-Ladona
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D049108:Cell Enlargement / Q000187:drug effects; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D062805:Synaptogyrins / Q000378:metabolism; D013747:Tetrabenazine / Q000494:pharmacology; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C493452:SLC18A2 protein, human; C497387:SREBF1 protein, human; C585899:SV2C protein, human; C540370:SYNGR3 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D062805:Synaptogyrins; D050493:Vesicular Monoamine Transport Proteins; D012110:Reserpine; D008148:Lovastatin; D004298:Dopamine; D013747:Tetrabenazine
keywords: DAT; Parkinson's disease; SREBP; VMAT2; cholesterol; dopamine; neurodifferentiation; neurotransmitter transport; nuclear translocation