Impact of LRRK2 Kinase Activity on Synaptic Vesicle Trafficking

Promising Outcomes of Original Grant:
Our previous work provided evidence that LRRK2 plays a crucial role in neurons by affecting the trafficking (movement across the cell) of synaptic vesicles (storage packets). Synaptic vesicle trafficking, including fusion, recycling and refilling, is instrumental for physiological neuronal activity and viability. We have shown that LRRK2 controls the mobilization of synaptic vesicles by interacting with other proteins. Our new data add one more level of complexity - the implication of LRRK2 kinase (protein regulation) activity within neurons. Our published observations suggest that LRRK2 kinase activity is involved in modifying dynamic synaptic vesicles.

Objectives for Supplemental Investigation:
Our previous work has shown that LRRK2 controls neuronal functions as a scaffold (structural support) and kinase. However, the molecular mechanism underlying LRRK2 mutations in Parkinson's is unclear. We have found an alteration in neuronal function in a LRRK2 G2019S pre-clinical model, in which LRRK2 G2019S kinase activity increases synaptic vesicle trafficking. Chronic administration of LRRK2 inhibitors partially reversed the effect without a major impact on healthy neurons. We now also know that LRRK2 interacts and phosphorylates (regulates) two key players involved in synaptic vesicle trafficking. Our aim is to investigate and possibly correct the functional consequences of LRRK2 pathological phosphorylation.

Importance of This Research for the Development of a New PD Therapy:
Accumulating evidence suggests that LRRK2 executes its primary function at the presynaptic site where it modifies synaptic vesicle trafficking. Robust data coming from pre-clinical models resemble early findings from LRRK2 mutation carriers and suggest that the G2019S mutation impacts neuronal function. Inhibition of the kinase activity of LRRK2 has been proposed as a possible treatment for Parkinson's disease. However, pre-clinical studies have described pulmonary toxicity as a critical safety liability for LRRK2 kinase inhibitors. We are confident that our effort to investigate the functional consequences of the G2019S mutation at the molecular level will support the development of alternative pharmacological approaches targeting LRRK2 dysfunction.