Neuron
Volume 75, Issue 6, 20 September 2012, Pages 1008-1021
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Article
LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis

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Summary

LRRK2 is a kinase mutated in Parkinson’s disease, but how the protein affects synaptic function remains enigmatic. We identified LRRK2 as a critical regulator of EndophilinA. Using genetic and biochemical studies involving Lrrk loss-of-function mutants and Parkinson-related LRRK2G2019S gain-of-kinase function, we show that LRRK2 affects synaptic endocytosis by phosphorylating EndoA at S75, a residue in the BAR domain. We show that LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association in vitro and in vivo and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo. Our work uncovers a regulatory mechanism that indicates that reduced LRRK2 kinase activity facilitates EndoA membrane association, while increased kinase activity inhibits membrane association. Consequently, both too much and too little LRRK2-dependent EndoA phosphorylation impedes synaptic endocytosis, and we propose a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses.

Highlights

► Both loss of LRRK and expression of LRRK2G2019S impede synaptic vesicle endocytosis ► LRRK2 phosphorylates EndoA at S75 and controls its membrane association ► S75 phosphorylation in the BAR domain inhibits membrane tubulation in vitro ► Increased and decreased EndoA S75 phosphorylation both inhibit synaptic endocytosis

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These authors contributed equally to this work