Investigation of the interplay between the Parkinson's disease-related proteins LRRK2 and VPS13C in cellular models and in Drosophila melanogaster

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by a wide range of motor and non-motor symptoms. The main hallmark of this pathology is represented by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). In addition to environmental factors, genetics plays an important role in PD onset, with 20 genes linked to familial forms of PD, including LRRK2, whose mutations cause autosomal dominant PD. LRRK2 is a multidomain enzyme, with kinase and GTPase activities, involved in the regulation of vesicle trafficking, cytoskeletal dynamics and lysosomal damage response. During a screening of the LRRK2 interactome, the protein VPS13C has been found to interact with LRRK2. VPS13C is mainly localized at the interface between the lysosomes/late endosomes and the ER and is involved in the organellar tethering and in lipid transport. Recently, VPS13C variants have been linked to the early-onset form of PD. This study aims at 1) dissecting the role of the interaction between LRRK2 and VPS13C in cellular models, with particular focus on the endolysosomal system, which is impaired in PD, and at 2) characterizing the effect of human LRRK2 and VPS13C PD variants in Drosophila melanogaster.