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

Authors :
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, Sandra‐Fausia
Source :
EMBO Journal. May2017, Vol. 36 Issue 10, p1392-1411. 20p. 2 Color Photographs, 4 Graphs.
Publication Year :
2017

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 Synaptojanin RQ 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 Synaptojanin RQ 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 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02614189
Volume :
36
Issue :
10
Database :
Academic Search Index
Journal :
EMBO Journal
Publication Type :
Academic Journal
Accession number :
123051032
Full Text :
https://doi.org/10.15252/embj.201695773