Thesis
English
ID: <
10670/1.1gcw5e>
Abstract
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 potential effects of statins on the synaptic expression and dopamine transport function in the dopaminergic system. In our studies, statins enhance the neurite outgrowth in the dopaminergic cells and trigger an increase in the expression levels of presynaptic dopaminergic proteins such as vesicular monoamine transporter 2 (VMAT2) and dopamine transporter. Statins induce a reduction of dopamine cellular uptake and modulate the binding-affinity of the specific inhibitors for VMAT2. The activation of the nuclear transcriptional factor sterol regulatory element-binding protein 1 (SREBP-1), cholesterol-dependent, could be the key element of the overexpression of dopaminergic presynaptic markers induced by the statins. Furthermore, these findings highlight the therapeutic neuroprotective and/or neurorestorative potentials of statins previously proposed in PD and allow to bring out new potential therapeutic targets such as SREBP factor.