Analysis of the effect of the Parkinson’s disease-linked VPS35 mutation on mitophagy

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder with a strongly increasing prevalence. No cure for PD exists yet. Therefore, it is important to further elucidate the pathogenic mechanisms of PD. A minority of PD cases have a monogenic cause. VPS35, LRRK2 and SNCA are genes linked to autosomal dominant PD. VPS35 is part of the retromer complex, which mediates the retrograde transport of proteins from the endosomal network to either the trans-Golgi network or the plasma membrane. The p.D620N missense mutation is the only known pathogenic mutation in VPS35. The molecular mechanisms by which this VPS35 mutation induces neurodegeneration are still unclear. Several monogenic causes of PD (PINK1, PRKN, LRRK2 mutations) have already been shown to disrupt the process of selective degradation of damaged mitochondria (mitophagy). The aim of this PhD is to investigate the possible role of wild-type VPS35 in mitophagy and the impact of the p.D620N mutation on this pathway. The experiments will be performed in patient and control skin fibroblasts, iPSC-derived dopaminergic neurons and Drosophila melanogaster.