EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation
Neuron. 2023-02-01; :
DOI: 10.1016/j.neuron.2023.02.001
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Bademosi AT(1), Decet M(2), Kuenen S(2), Calatayud C(2), Swerts J(2), Gallego SF(2), Schoovaerts N(2), Karamanou S(3), Louros N(4), Martin E(5), Sibarita JB(6), Vints K(7), Gounko NV(7), Meunier FA(8), Economou A(3), Versées W(5), Rousseau F(4), Schymkowitz J(4), Soukup SF(9), Verstreken P(10).
Author information:
(1)VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Mission Lucidity, Leuven 3000, Belgium; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia.
(2)VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Mission Lucidity, Leuven 3000, Belgium.
(3)KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven 3000, Belgium.
(4)VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; witch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
(5)VIB-VUB Center for Structural Biology, Brussels 1050, Belgium; Department of Structural Biology Brussels, Vrije Universiteit Brussel, Brussels 1050, Belgium. (6)Interdisciplinary Institute for Neuroscience, University of Bordeaux, F-33000 Bordeaux, France.
(7)VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Mission Lucidity, Leuven 3000, Belgium; VIB Bio Core, KU Leuven, Leuven 3000, Belgium.
(8)Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia.
(9)Univ. Bordeaux, CNRS UMR 5293, F-33000 Bordeaux, France. Electronic address: .
(10)VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Mission Lucidity, Leuven 3000, Belgium. Electronic address: .
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.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement: Declaration of interests P.V. is the scientific
founder of Jay Therapeutics. All other authors declare no competing interests.