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

Neuron. 2016 Nov 23;92(4):829-844. doi: 10.1016/j.neuron.2016.09.037. Epub 2016 Oct 6.


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.

MeSH terms

  • Acyltransferases / metabolism*
  • Animals
  • Autophagosomes / metabolism*
  • Autophagy / genetics*
  • Autophagy-Related Proteins / metabolism*
  • Dopaminergic Neurons / metabolism*
  • Drosophila
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Endocytosis
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Neurodegenerative Diseases
  • Phosphorylation / genetics
  • Presynaptic Terminals / metabolism*
  • Synaptic Vesicles / metabolism


  • Autophagy-Related Proteins
  • Drosophila Proteins
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase
  • LRRK2 protein, Drosophila
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2