LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis

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• 作者：Samer Matta ; Kristof Van?Kolen ; Raquel da?Cunha ; Geert van?den?Bogaart ; Wim M ; emakers ; Katarzyna Miskiewicz ; Pieter-Jan De?Bock ; Vanessa?A. Morais ; Sven Vilain ; Dominik Haddad ; Lore Delbroek ; Jef Swerts ; Luc¨ªa Ch¨¢vez-Guti¨¦rrez ; Giovanni Esposito ; Guy Daneels ; Eric Karran ; Matthew Holt ; Kris Gevaert ; Diederik?W. Moechars ; Bart De?Strooper ; et al.
• 刊名：Neuron
• 出版年：2012
• 出版时间：20 September, 2012
• 年：2012
• 卷：75
• 期：6
• 页码：1008-1021
• 全文大小：2302 K

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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 LRRK2^G2019S 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.