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The SAC 1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals
Author(s) -
Vanhauwaert Roeland,
Kuenen Sabine,
Masius Roy,
Bademosi Adekunle,
Manetsberger Julia,
Schoovaerts Nils,
Bounti Laura,
Gontcharenko Serguei,
Swerts Jef,
Vilain Sven,
Picillo Marina,
Barone Paolo,
Munshi Shashini T,
Vrij Femke MS,
Kushner Steven A,
Gounko Natalia V,
Mandemakers Wim,
Bonifati Vincenzo,
Meunier Frederic A,
Soukup SandraFausia,
Verstreken Patrik
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695773
Subject(s) - synaptic vesicle recycling , biology , microbiology and biotechnology , synaptic vesicle , autophagy , synapse , neurodegeneration , endocytosis , biochemistry , neuroscience , vesicle , receptor , apoptosis , medicine , disease , membrane
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)P 2 , but this function appears normal in Synaptojanin RQ knock‐in flies. Instead, R258Q affects the synaptojanin SAC 1 domain that dephosphorylates PI (3)P and PI (3,5)P 2 , two lipids found in autophagosomal membranes. Using advanced imaging, we show that Synaptojanin RQ mutants accumulate the PI (3)P/ PI (3,5)P 2 ‐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 Synaptojanin RQ 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.