Progetto LRRK2-SV

  • Impact of LRRK2 kinase activity on synaptic vesicle trafficking

Mutations in LRRK2 are the most common genetic cause of PD, accounting for up to 13% of familiar cases with dominant inheritance and 1 to 2% of sporadic PD patients. We have previously observed that LRRK2 kinase activity influences presynaptic SV release via phosphorylation of its presynaptic targets. However, the detailed molecular mechanism correlating LRRK2 kinase activity to synaptic vesicle (SV) remain unclear. In this project we plan to detail this phenomenon at the molecular level. Given that the most diffuse LRRK2 mutation, the G2019S substitution, is associated with increased kinase activity, an ineluctable question is: how do LRRK2 mutations impact presynaptic functions? We aim to achieve two main goals: to assess the impact of LRRK2 phosphorylation on presynaptic targets activity, and to disclose the functional outcomes of such phosphorylation events at the synapse.

To this aim, we have started to analyse synaptic properties in BAC G2019S mice. Our preliminary observations suggest that mutant LRRK2 correlates with altered neuronal functions. We plan to execute functional studies to investigate the impact of G2019S mutation.

Independent evidences correlate LRRK2 to SV trafficking and, interestingly, an increased dopamine turnover has been described also in LRRK2 mutation carriers. Thus defects of SV trafficking in dopaminergic neurons might severely contribute to Parkinson’s disease (PD) progression. Our aims are not only to provide critical information about the physiological role of LRRK2 but also to pave the way to understand the implication of LRRK2 during PD progression and to evaluate the potential feasibility of pharmacological approaches targeting LRRK2 kinase activity.

Principal Investigators