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

Autor: Vanhauwaert R; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Kuenen S; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Masius R; Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands., Bademosi A; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia., Manetsberger J; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Schoovaerts N; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Bounti L; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Gontcharenko S; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Swerts J; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Vilain S; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Picillo M; Department of Medicine and Surgery, Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Salerno, Italy., Barone P; Department of Medicine and Surgery, Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Salerno, Italy., Munshi ST; Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands., de Vrij FM; Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands., Kushner SA; Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands., Gounko NV; VIB Center for Brain & Disease Research, Leuven, Belgium.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium.; Electron Microscopy Platform, VIB Bio-Imaging Core, Leuven, Belgium., Mandemakers W; Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands., Bonifati V; Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands., Meunier FA; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia., Soukup SF; VIB Center for Brain & Disease Research, Leuven, Belgium sandra.soukup@cme.vib-kuleuven.be patrik.verstreken@cme.vib-kuleuven.be.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium., Verstreken P; VIB Center for Brain & Disease Research, Leuven, Belgium sandra.soukup@cme.vib-kuleuven.be patrik.verstreken@cme.vib-kuleuven.be.; Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2017 May 15; Vol. 36 (10), pp. 1392-1411. Date of Electronic Publication: 2017 Mar 22.
DOI: 10.15252/embj.201695773
Abstrakt: 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 SAC1 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.
(© 2017 The Authors.)
Databáze: MEDLINE
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