EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Neuron. 2023 May 3;111(9):1402-1422.e13. doi: 10.1016/j.neuron.2023.02.001. Epub 2023 Feb 23.


Neuronal activity causes use-dependent decline in protein function. However, it is unclear how this is coupled to local quality control mechanisms. We show in Drosophila that the endocytic protein Endophilin-A (EndoA) connects activity-induced calcium influx to synaptic autophagy and neuronal survival in a Parkinson disease-relevant fashion. Mutations in the disordered loop, including a Parkinson disease-risk mutation, render EndoA insensitive to neuronal stimulation and affect protein dynamics: when EndoA is more flexible, its mobility in membrane nanodomains increases, making it available for autophagosome formation. Conversely, when EndoA is more rigid, its mobility reduces, blocking stimulation-induced autophagy. Balanced stimulation-induced autophagy is required for dopagminergic neuron survival, and a variant in the human ENDOA1 disordered loop conferring risk to Parkinson disease also blocks nanodomain protein mobility and autophagy both in vivo and in human-induced dopaminergic neurons. Thus, we reveal a mechanism that neurons use to connect neuronal activity to local autophagy and that is critical for neuronal survival.

Keywords: Ca(2+) influx; Parkinson disease; endophilinA; neuronal activity; synaptic autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics
  • Calcium / metabolism
  • Dopaminergic Neurons / metabolism
  • Drosophila / metabolism
  • Humans
  • Mutation / genetics
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism


  • Calcium
  • SH3GL2 protein, human
  • endophilin A, Drosophila