Abstract
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) produce the most common inherited form of Parkinson’s disease (PD) but the function of LRRK2 remains poorly understood. The presynaptic role of multiple genes linked to PD including α-synuclein (α-syn) has suggested that LRRK2 may also influence neurotransmitter release, a possibility supported by recent work. However, the use of disease-associated mutants that cause toxicity complicates the analysis. To determine whether LRRK2 normally influences the synaptic vesicle, we have now used a combination of imaging and electrophysiology to study LRRK2 knockout (KO) mice. Surprisingly, we find that in hippocampal (generally excitatory) neurons, the loss of LRRK2 does not affect synaptic vesicle exocytosis, endocytosis or the mobility of α-syn. Double KO (DKO) mice lacking LRRK1 as well as LRRK2 also show no defect in transmitter release by hippocampal neurons. However, in striatal neurons, which express LRRK2 at higher levels, the loss of LRRK2 leads to modest acceleration of synaptic vesicle endocytosis. Thus, endogenous LRRK2 normally slows synaptic vesicle recycling at striatal terminals.
Highlights
Parkinson’s disease (PD) is defined by the loss of dopamine neurons in the substantia nigra, accumulating evidence suggests that pathology originates at the nerve terminal (Nakata et al, 2012; Janezic et al, 2013)
We assessed release probability using the paired-pulse ratio (PPR), which shows no effect of the leucine-rich repeat kinase 2 (LRRK2) KO except at the 20 ms interstimulus interval, suggesting little or no effect on neurotransmitter release (Figure 1B)
The results indicate that LRRK2 has a modest inhibitory effect on endocytosis in striatal but not hippocampal neurons
Summary
Parkinson’s disease (PD) is defined by the loss of dopamine neurons in the substantia nigra, accumulating evidence suggests that pathology originates at the nerve terminal (Nakata et al, 2012; Janezic et al, 2013). In contrast to the rare mutations in α-syn, synaptojanin and auxilin, dominant mutations in leucine-rich repeat kinase 2 (LRRK2) produce the most common form of inherited PD and up to 10% of sporadic disease (Healy et al, 2008). Since the pathology resulting from LRRK2 mutations usually involves deposition of α-syn (Giasson et al, 2006), it is possible that LRRK2, like α-syn, modulates neurotransmitter release, and that mutant LRRK2 causes disease through a presynaptic mechanism, possibly involving synuclein
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
