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LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis.

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.

Pubmed ID: 22998870


  • Matta S
  • Van Kolen K
  • da Cunha R
  • van den Bogaart G
  • Mandemakers W
  • Miskiewicz K
  • De Bock PJ
  • Morais VA
  • Vilain S
  • Haddad D
  • Delbroek L
  • Swerts J
  • Chávez-Gutiérrez L
  • Esposito G
  • Daneels G
  • Karran E
  • Holt M
  • Gevaert K
  • Moechars DW
  • De Strooper B
  • Verstreken P



Publication Data

September 20, 2012

Associated Grants


Mesh Terms

  • Acyltransferases
  • Animals
  • Animals, Genetically Modified
  • Brain
  • CHO Cells
  • Calcium
  • Clathrin
  • Cricetinae
  • Drosophila
  • Drosophila Proteins
  • Endocytosis
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Humans
  • Mass Spectrometry
  • Mice
  • Microscopy, Electron, Transmission
  • Models, Molecular
  • Mutation
  • Neuromuscular Junction
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • RNA, Small Interfering
  • Sequence Alignment
  • Serine
  • Synaptic Potentials
  • Synaptic Vesicles
  • Transfection