Modulation of the expression and function of dopaminergic presynaptic proteins by the statins: potential implication for the therapeutic intervention in Parkinson's diseasedécembre 2015 Directeur(s) de thèse : Erwan BEZARD Résumé de thèse
Parkinson disease (PD) is characterized by a progressive loss of dopaminergic presynaptic terminals and remains incurable. However in epidemiological studies, it has been shown that the use of statins, which are hypocholesterolemic drugs, diminishes the risk to develop a PD. Statins are able to inhibit the neurodegenerative effects in in-vitro and in-vivo models of PD. However, the molecular mechanisms driving neuroprotective effects are not yet fully understood.
Consequently, we investigated the pleitrophic potential of statins and their impacts on synaptic expression and dopamine transport function in the dopaminergic system. In our studies, statins induced neurite outgrowth in SH-SY5Y neuroblastoma cells and triggered an increase in the levels of presynaptic dopaminergic proteins and mRNA such as synaptogyrin 3 (SYNGR3), vesicular monoamine transporter 2 (VMAT2), synaptic vesicle glycoprotein isoforms 2A and 2C, dopamine transporter (DAT) and tyrosine hydroxylase. DAT and VMAT2 are key players in dopaminergic presynaptic regulation and the pharmacologic components of these transporter are affected the statins. They induce a reduction of dopamine cellular uptake and a change the affinity for binding site of the VMAT2 inhibitors. In order to identify the potential mechanism at the base of the observed gene expression, we investigated the role of the sterol regulatory element-binding protein 1 (SREBP-1), a cholesterol-dependent nuclear transcription factor. Our data suggests that a cholesterol-dependent downstream gene expression pathway may modulate dopaminergic presynaptic system.
Overall, these findings highlight a potential mechanism of statins action on the modulation of the dopaminergic system. Furthermore, they confirm and extend the therapeutic neuroprotective and/or neurorestorative potentials of statins in PD and allow to bring out new potential therapeutic targets such as SREBP factor.