The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals

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., de Vrij, Femke M. S., Kushner, Steven A., Gounko, Natalia V., Mandemakers, Wim, Bonifati, Vincenzo, Meunier, Frederic A., Soukup, Sandra‐Fausia and Verstreken, Patrik (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

Author 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.
de Vrij, Femke M. S.
Kushner, Steven A.
Gounko, Natalia V.
Mandemakers, Wim
Bonifati, Vincenzo
Meunier, Frederic A.
Soukup, Sandra‐Fausia
Verstreken, Patrik
Title The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals
Journal name EMBO Journal   Check publisher's open access policy
ISSN 1460-2075
Publication date 2017-04-03
Year available 2017
Sub-type Article (original research)
DOI 10.15252/embj.201695773
Open Access Status Not yet assessed
Volume 36
Issue 10
Start page 1392
End page 1411
Total pages 20
Place of publication Chichester, West Sussex United Kingdom
Publisher Wiley
Collection year 2018
Language eng
Formatted 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.
Keyword Correlative light and electron microscopy
Induced pluripotent stem cells
Parkinson's disease
Single-molecule tracking
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
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