期刊
JOURNAL OF CELL SCIENCE
卷 128, 期 3, 页码 541-552出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.158196
关键词
LRRK2; Endophilin A1; Endocytosis
类别
资金
- Agency for Innovation by Science and Technology (IWT-Flanders) [100508]
- European Research Council (ERC)
- Fonds voor Wetenschappelijk Onderzoek (FWO)
- KULeuven
- Flemish Institute for Biotechnology (VIB)
- KULeuven/Flemish Government
- Bax-Vanluffelen chair for Alzheimer's Disease
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions. Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1, also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.
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