Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Calcium / metabolism
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Cells, Cultured
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Cerebral Cortex / ultrastructure*
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Electric Stimulation / methods
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Embryo, Mammalian
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Gene Expression Regulation, Developmental / genetics
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Humans
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Immunoprecipitation / methods
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Mice
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Microscopy, Electron, Transmission
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Mutation / genetics
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N-Ethylmaleimide-Sensitive Proteins / metabolism
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Nerve Tissue Proteins / metabolism
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Neurons / cytology*
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Patch-Clamp Techniques / methods
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Potassium Chloride / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Protein Transport / drug effects
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Protein Transport / genetics
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RNA, Small Interfering / pharmacology
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Sodium Channel Blockers / pharmacology
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Synapses / ultrastructure*
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Synaptic Vesicles / drug effects
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Synaptic Vesicles / physiology*
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Synaptic Vesicles / ultrastructure
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Synaptosomes / metabolism
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Tandem Mass Spectrometry / methods
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Tetrodotoxin / pharmacology
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Transfection / methods
Substances
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Nerve Tissue Proteins
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RNA, Small Interfering
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Sodium Channel Blockers
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Tetrodotoxin
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Potassium Chloride
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LRRK2 protein, human
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Protein Serine-Threonine Kinases
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N-Ethylmaleimide-Sensitive Proteins
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Nsf protein, mouse
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Calcium