Grant: Project Grant

Parkinson's disease (PD) is a progressive neurodegenerative brain disorder that causes a range of motor and non-motor symptoms. Some of the major symptoms of PD are caused by the loss of a class of neurons using the chemical messenger dopamine (DA). There is also a large reduction in the density of DA-containing axon terminals. It has been proposed that loss of terminals may precede the loss of cell bodies, a hypothesis called "dying-back". The specific trigger of the early degeneration of DA-containing axonal terminals is unclear. In a recent publication, we discovered that two genes associated with familial forms of PD, Parkin and Pink1, also negatively regulate the presentation of mitochondrial proteins to the immune system, suggesting that forms of PD associated with mutations in these genes may implicate auto-immune mechanisms. Based on exciting recent data obtained by our team showing that gut infection of mice in which the Pink1 gene has been inactivated (KO), leads to the production of cytotoxic immune cells and to loss of DA-containing axon terminals, but not to loss of cell bodies, we propose here that auto-immune mechanisms and inflammatory signals may cause a selective attack on DA-containing axon terminals, perhaps providing a first insight into a mechanism triggering the dying back of terminals in PD. In the present application, we propose here three series of experiments to better document the model and test the hypothesis that following an infection in Pink1 KO mice, inflammatory signals and cytotoxic immune cells recognizing mitochondrial proteins directly affect the integrity of DA-containing axon terminals. This project, performed by a team of complementary investigators has the potential to shed light on a key, early mechanism of PD pathophysiology, paving the way to new potential strategies to slow down or halt the progression of PD.