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

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
EMBO J.. 2017-03-22; 36(10): 1392-1411
DOI: 10.15252/embj.201695773

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1. EMBO J. 2017 May 15;36(10):1392-1411. doi: 10.15252/embj.201695773. Epub 2017 Mar

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

Vanhauwaert R(1)(2), Kuenen S(1)(2), Masius R(3), Bademosi A(4), Manetsberger
J(1)(2), Schoovaerts N(1)(2), Bounti L(1)(2), Gontcharenko S(1)(2), Swerts
J(1)(2), Vilain S(1)(2), Picillo M(5), Barone P(5), Munshi ST(6), de Vrij FM(6),
Kushner SA(6), Gounko NV(1)(2)(7), Mandemakers W(3), Bonifati V(3), Meunier
FA(4), Soukup SF(8)(2), Verstreken P(8)(2).

Author information:
(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.
(8)VIB Center for Brain & Disease Research, Leuven, Belgium

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.

© 2017 The Authors.

DOI: 10.15252/embj.201695773
PMCID: PMC5430236
PMID: 28331029 [Indexed for MEDLINE]

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