The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals |
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| Authors: | Roeland Vanhauwaert Sabine Kuenen Roy Masius Adekunle Bademosi Julia Manetsberger Nils Schoovaerts Laura Bounti Serguei Gontcharenko Jef Swerts Sven Vilain Marina Picillo Paolo Barone Shashini T Munshi Femke MS de Vrij Steven A Kushner Natalia V Gounko Wim Mandemakers Vincenzo Bonifati Frederic A Meunier Sandra‐Fausia Soukup Patrik Verstreken |
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| Affiliation: | 1. VIB Center for Brain & Disease Research, Leuven, Belgium;2. Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium;3. Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands;4. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia;5. Department of Medicine and Surgery, Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Salerno, Italy;6. Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands;7. Electron Microscopy Platform, VIB Bio‐Imaging Core, Leuven, Belgium |
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| Abstract: | Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock‐in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advanced imaging, we show that SynaptojaninRQ mutants accumulate the PI(3)P/PI(3,5)P2‐binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell‐derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in SynaptojaninRQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic‐specific autophagy defects to Parkinson's disease. |
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| Keywords: | correlative light and electron microscopy induced pluripotent stem cells Parkinson's disease single‐molecule tracking synapse |
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