The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals
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.
|Keywords||Correlative light and electron microscopy, Induced pluripotent stem cells, Parkinson's disease, Single-molecule tracking, Synapse|
|Persistent URL||dx.doi.org/10.15252/embj.201695773, hdl.handle.net/1765/98952|
|Grant||This work was funded by the European Commission 7th Framework Programme; grant id erc/646671 - Maintaining synaptic function for a healthy brain: Membrane trafficking and autophagy in neurodegeneration (RobustSynapses)|
Vanhauwaert, R, Kuenen, S, Masius, R.G, Bademosi, A, Manetsberger, J, Schoovaerts, N, … Verstreken, P. (2017). The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals. EMBO Journal, 36(10), 1392–1411. doi:10.15252/embj.201695773