SAN2020

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons of the substantia nigra and the intracellular accumulation of α-synuclein (AS) in Lewy bodies. While the pathogenic mechanisms of PD is still debated, many lines of evidence point to a role of intracellular trafficking defects. Increased expression of AS is associated with a higher incidence of PD, but we know little about the molecular mechanisms induced by AS that precede neurodegeneration. We use an innovative exocytic pathway synchronization system which allows coordinated release of transmembrane proteins from the endoplasmic reticulum (ER) using a specific drug. This tool enable us to study whether AS affects the dynamics of vesicular transport between the ER and the Golgi apparatus, and the release of vesicles from the latter towards neural processes. We found that AS expression induces a delay in vesicles release from the Golgi apparatus to neuronal processes in hippocampal neurons. This result suggests a possible mechanism by which AS generates toxicity that may have consequences on neuronal physiology. We are currently working to assess whether the same effect is present in human reprogrammed neurons derived from induced pluripotent stem cells (iPSC).