title: A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.
abstract: Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turn over proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated. EndophilinA-phosphorylation promotes the formation of highly curved membranes, and reconstitution experiments show these curved membranes serve as docking stations for autophagic factors, including Atg3. Functionally, deregulation of the EndophilinA phosphorylation state accelerates activity-induced neurodegeneration. Given that EndophilinA is connected to at least three Parkinson's disease genes (LRRK2, Parkin and Synaptojanin), dysfunction of EndophilinA-dependent synaptic macroautophagy may be common in this disorder.
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Sandra-Fausia
authors.initials: SF
authors.lastname: Soukup
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuenen
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Roeland
authors.initials: R
authors.lastname: Vanhauwaert
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Julia
authors.initials: J
authors.lastname: Manetsberger
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hernández-Díaz
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Swerts
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Nils
authors.initials: N
authors.lastname: Schoovaerts
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Vilain
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Gounko
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Katlijn
authors.initials: K
authors.lastname: Vints
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Geens
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium. Electronic address: patrik.verstreken@cme.vib-kuleuven.be.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004705:Endocytosis; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases; D010766:Phosphorylation / Q000235:genetics; D017729:Presynaptic Terminals / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases
chemical_list: D000217:Acyltransferases; D000071183:Autophagy-Related Proteins; D029721:Drosophila Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C018764:2-acylglycerophosphate acyltransferase; C543697:LRRK protein, Drosophila; D017346:Protein Serine-Threonine Kinases