Funded Studies
This grant builds upon the research from a prior grant: Impact of LRRK2 Kinase Activity on Synaptic Vesicle Trafficking
Objective/Rationale:
Synapses provide a connection that allows signals to travel between neurons. Pre-clinical research showed that the LRRK2 kinase may influence synaptic function through effects on presynaptic proteins (which prepare the synapses for the release of neurotransmitters). A previous MJFF-funded project from this group showed that LRRK2 kinase activity is also involved in modulating synaptic properties. This project seeks to understand LRRK2 function and interaction at the presynaptic site.
Project Description:
The molecular mechanism that connects LRRK2 activity with synaptic vesicles remains unclear, but data suggest that LRRK2 activity influences synaptic vesicle release. Of interest is that LRRK2 interacts with NSF and synapsin 1. NSF is an enzyme that permits the disassembly of the SNARE complex, allowing synaptic vesicle cycling. The researchers will study the impact of LRRK2 kinase activity on SNARE complex stability. Synapsin 1 is a protein that tethers synaptic vesicles to a cell’s structure, and the interaction among LRRK2, synapsin 1 and synaptic vesicles is modulated by LRRK2 activity. They’ll detail this phenomenon at the molecular level.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Research correlates LRRK2 with synaptic vesicle release and, interestingly, an increased dopamine turnover has been described also in LRRK2 mutation carriers. Thus defects of synaptic vesicle trafficking in dopaminergic neurons might severely contribute to Parkinson’s disease progression. This project could lead to greater understanding of the role of LRRK2 in Parkinson’s progression and, ultimately, to pharmacological approaches targeting LRRK2 kinase activity.
Anticipated Outcome:
We aim to achieve two main goals: to assess the impact of LRRK2 on NSF and synapsin 1 activity and to observe the functional outcomes of interaction at the synapse.
Final Outcome
In this project we investigated the impact of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced synaptic activity, the rate of synaptic vesicle trafficking and the release of neurotransmitter. Our previous observation suggested LRRK2 phosphorylates two proteins executing key processes at the presynaptic bouton, namely NSF and synapsin I. However, wild-type LRRK2 kinase activity does not influence presynaptic function via modulation of NSF and synapsin I. Instead we demonstrated that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex. The most common G2019S mutation increases LRRK2 kinase activity. Intriguingly, we found that LRRK2 G2019S phosphorylation influences the biochemical properties of NSF and synapsin I. These findings leave space for the possibility that mutant LRRK2 influences synaptic function through gain-of-function effects on synaptic proteins.