title: Endogenous Leucine-Rich Repeat Kinase 2 Slows Synaptic Vesicle Recycling in Striatal Neurons.
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.
authors.affiliation: Departments of Neurology and Physiology, Weill Institute for Neurosciences, and Kavli Institute for Fundamental Neuroscience, UCSF School of Medicine San Francisco, CA, USA.
authors.forename: James W Jr
authors.initials: JW
authors.lastname: Maas
authors.affiliation: Departments of Neurology and Physiology, Weill Institute for Neurosciences, and Kavli Institute for Fundamental Neuroscience, UCSF School of Medicine San Francisco, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Departments of Neurology and Physiology, Weill Institute for Neurosciences, and Kavli Institute for Fundamental Neuroscience, UCSF School of Medicine San Francisco, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
keywords: LRRK2; Parkinson’s disease; endocytosis; striatum; synaptic vesicle