The role of p.D620N VPS35 patient-derived microglia in Parkinson’s disease pathophysiology

Parkinson’s disease (PD) is the second most common neurodegenerative disease. One of the genes that is strongly related to PD is VPS35. VPS35 is involved in the intracellular sorting and trafficking of numerous proteins and our group has confirmed that the D620N VPS35 mutation is associated with increased α-synuclein levels, due to decreased autophagic flux, and significant mitochondrial dysfunction in patient-derived dopaminergic neurons. Recently, a number of reports have linked VPS35 KO to altered inflammatory profile and microglia activation in models of Alzheimer's disease and ischemic stroke. However, no studies so far have assessed the roles of microglial VPS35 in PD.
With this project, we aim to identify the role of D620N VPS35 mutation in microglial functions and inflammatory regulation, focusing on phagocytosis efficiency and cytokine production, as well as lysosomal and mitochondrial functions. Based on our findings, we will identify new ‘’signature’’ pathways that can serve as putative therapeutic targets in co-culture studies. To our knowledge, this is the first study to focus on the roles of mutant VPS35 in patient-derived microglia, and as such, we are confident to provide new perspectives from a defined monogenic model of PD for future studies aiming to decipher immune mechanisms in PD.