TY - JOUR
T1 - EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation
AU - Bademosi, Adekunle T.
AU - Decet, Marianna
AU - Kuenen, Sabine
AU - Calatayud, Carles
AU - Swerts, Jef
AU - Gallego, Sandra F.
AU - Schoovaerts, Nils
AU - Karamanou, Spyridoula
AU - Louros, Nikolaos
AU - Martin, Ella
AU - Sibarita, Jean Baptiste
AU - Vints, Katlijn
AU - Gounko, Natalia V.
AU - Meunier, Frédéric A.
AU - Economou, Anastassios
AU - Versées, Wim
AU - Rousseau, Frederic
AU - Schymkowitz, Joost
AU - Soukup, Sandra F.
AU - Verstreken, Patrik
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/5/3
Y1 - 2023/5/3
N2 - 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.
AB - 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.
KW - Ca influx
KW - endophilinA
KW - neuronal activity
KW - Parkinson disease
KW - synaptic autophagy
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UR - http://www.scopus.com/inward/citedby.url?scp=85150256233&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2023.02.001
DO - 10.1016/j.neuron.2023.02.001
M3 - Article
C2 - 36827984
AN - SCOPUS:85150256233
SN - 0896-6273
VL - 111
SP - 1402-1422.e13
JO - Neuron
JF - Neuron
IS - 9
ER -