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A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals
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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“LRRK2 activity plays a role in synaptic vesicle endocytosis, activation of autophagy, and axonal transport of growth factor receptors [2, 7, 10, 24, 25, 36, 51, 59, 62, 75, 77, 96].”
From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [75]
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Self-citationSynaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson’s Disease
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“In Drosophila, autophagosome biogenesis also occurred at the neuromuscular junction (NMJ) in the distal axon of motor neurons (Neisch et al. 2017, Soukup et al. 2016).”
BackgroundKuijpers, M., Kochlamazashvili, G., Stumpf, A., Puchkov, D., Swaminathan, A., Lucht, M. T., Krause, E., Maritzen, T., Schmitz, D., & Haucke, V. (2021) · Neuron · doi:10.1016/j.neuron.2020.10.005 · Cited by 170
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Background
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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