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A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals

Soukup, Sandra-Fausia, Kuenen, Sabine, Vanhauwaert, Roeland, Manetsberger, Julia, Hernández-Díaz, Sergio, Swerts, Jef, Schoovaerts, Nils, Vilain, Sven, Gounko, Natalia V., Vints, Katlijn, Geens, Ann, De Strooper, Bart, Verstreken, Patrik·2016·Neuron

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.

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Metadata

Authors
Soukup, S.-F., Kuenen, S., Vanhauwaert, R., Manetsberger, J., Hernández-Díaz, S., Swerts, J., Schoovaerts, N., Vilain, S., Gounko, N. V., Vints, K., Geens, A., De Strooper, B., & Verstreken, P.
Venue
Neuron
Publisher
Elsevier BV
Published
2016-11
Volume
92
Issue
4
Pages
829-844
ISSN
0896-6273
Cited by
293
References
5
Language
en

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