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Neuroscience

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    OH MYeloid! Immune cells wreaking havoc on brain homeostasis
    OH MYeloid! Immune cells wreaking havoc on brain homeostasis
    1. Liana Bonanno1 and
    2. Tony Wyss‐Coray (twc{at}stanford.edu)2,3,4
    1. 1Stanford Neurosciences Graduate Training Program, Stanford University School of Medicine, Stanford, CA, USA
    2. 2Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
    3. 3Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Healthcare System, Palo Alto, CA, USA
    4. 4Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA

    Genetic mutations responsible for neurodegenerative Nasu‐Hakola disease have been localized to the gene TREM2 and its adaptor DAP12, but it remained unclear what causes the brain to deteriorate. In this issue of The EMBO Journal, Kleinberger et al (2017) provide intriguing evidence suggesting a TREM2 mutation alone can lead to striking microglial dysfunction and precipitate changes in cerebral blood flow and metabolism in mice.

    See also: G Kleinberger et al (July 2017)

    New mouse models show that dementia‐associated TREM2 mutation can cause microglial dysfunction and precipitate changes in cerebral blood flow and metabolism.

    • © 2017 The Authors
    Liana Bonanno, Tony Wyss‐Coray
    Published online 03.07.2017
    • Metabolism
    • Molecular Biology of Disease
    • Neuroscience
  • You have access
    The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
    The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
    1. Gernot Kleinberger1,2,
    2. Matthias Brendel3,
    3. Eva Mracsko4,
    4. Benedikt Wefers5,6,
    5. Linda Groeneweg4,
    6. Xianyuan Xiang1,
    7. Carola Focke3,
    8. Maximilian Deußing3,
    9. Marc Suárez‐Calvet1,5,
    10. Fargol Mazaheri5,
    11. Samira Parhizkar1,
    12. Nadine Pettkus1,
    13. Wolfgang Wurst2,5,6,7,
    14. Regina Feederle2,5,8,
    15. Peter Bartenstein2,3,
    16. Thomas Mueggler4,
    17. Thomas Arzberger5,9,10,
    18. Irene Knuesel4,
    19. Axel Rominger2,3 and
    20. Christian Haass (christian.haass{at}mail03.med.uni-muenchen.de)*,1,2,5
    1. 1Biomedical Center (BMC), Biochemistry, Ludwig‐Maximilians‐Universität München, Munich, Germany
    2. 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
    3. 3Department of Nuclear Medicine, Ludwig‐Maximilians‐Universität München, Munich, Germany
    4. 4NORD Discovery & Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    5. 5German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    6. 6Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
    7. 7Technische Universität München, Freising‐Weihenstephan, Germany
    8. 8Helmholtz Center Munich, German Research Center for Environmental Health, Institute for Diabetes and Obesity, Core Facility Monoclonal Antibody Development, Munich, Germany
    9. 9Center for Neuropathology and Prion Research, Ludwig‐Maximilians‐Universität München, Munich, Germany
    10. 10Department of Psychiatry and Psychotherapy, Ludwig‐Maximilians‐Universität München, Munich, Germany
    1. ↵*Corresponding author. Tel: +49 89 4400 46549; E‐mail: christian.haass{at}mail03.med.uni-muenchen.de

    A knock‐in mouse model of the frontotemporal dementia disease‐associated TREM2 mutation, p.T66M, shows a loss‐of‐function phenotype with age‐dependent reduction in microglial activity and systemic metabolic alterations throughout the brain.

    Synopsis

    Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous endogenous expression of the TREM2 p.T66M mutation impairs microglia function, brain perfusion and glucose metabolism, suggesting that microglial TREM2 acts as a signaling hub.

    • Trem2 p.T66M knock‐in mice show delayed resolution of inflammation.

    • Trem2 p.T66M knock‐in mice exhibit decreased age‐dependent microglial activity.

    • Trem2 p.T66M knock‐in mice show reduced cerebral blood flow.

    • Trem2 p.T66M knock‐in mice show reduced glucose metabolism.

    • frontotemporal dementia
    • neurodegeneration
    • neuroinflammation
    • regulated intramembrane proteolysis
    • TREM2

    The EMBO Journal (2017) 36: 1837–1853

    • Received January 12, 2017.
    • Revision received April 21, 2017.
    • Accepted April 27, 2017.
    • © 2017 The Authors
    Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez‐Calvet, Fargol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger, Christian Haass
    Published online 03.07.2017
    • Metabolism
    • Molecular Biology of Disease
    • Neuroscience
  • You have access
    PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila
    PAR‐1 promotes microtubule breakdown during dendrite pruning in <em>Drosophila</em>
    1. Svende Herzmann1,
    2. Rafael Krumkamp1,
    3. Sandra Rode1,
    4. Carina Kintrup1 and
    5. Sebastian Rumpf (sebastian.rumpf{at}uni-muenster.de)*,1
    1. 1Institute for Neurobiology, University of Münster, Münster, Germany
    1. ↵*Corresponding author. Tel: +49 251 8322390; E‐mail: sebastian.rumpf{at}uni-muenster.de

    Severing of unspecific neurites during neuronal morphogenesis is facilitated by PAR‐1‐mediated Tau phosphorylation, which increases microtubule dynamics prior to disassembly.

    Synopsis

    The developmental elimination of long stretches of neurite during neuronal morphogenesis—also known as pruning—involves the disassembly of microtubules in affected neurites. Using genetic and imaging analyses of dendrite pruning in Drosophila, we found that microtubule disruption is driven by the kinase PAR‐1, likely via an inhibitory effect on Tau.

    • Mutation or knockdown of PAR‐1 leads to dendrite pruning defects.

    • Loss of PAR‐1 prevents microtubule disruption during pruning.

    • PAR‐1 increases microtubule dynamics at the onset of pruning.

    • Genetic analysis suggests Tau is the relevant PAR‐1 target.

    • PAR‐1 is also required for subsequent membrane collapse.

    • dendrite
    • PAR‐1
    • pruning
    • Tau

    The EMBO Journal (2017) 36: 1981–1991

    • Received October 15, 2016.
    • Revision received April 21, 2017.
    • Accepted April 26, 2017.
    • © 2017 The Authors
    Svende Herzmann, Rafael Krumkamp, Sandra Rode, Carina Kintrup, Sebastian Rumpf
    Published online 03.07.2017
    • Cell Adhesion, Polarity & Cytoskeleton
    • Neuroscience
  • Open Access
    Is magnetogenetics the new optogenetics?
    Is magnetogenetics the new optogenetics?
    1. Simon Nimpf1 and
    2. David A Keays (keays{at}imp.ac.at)1
    1. 1Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria

    Optogenetics has revolutionised neuroscience as it enables investigators to establish causal relationships between neuronal activity and a behavioural outcome in a temporally precise manner. It is a powerful technology, but limited by the necessity to deliver light to the cells of interest, which often requires invasive surgery and a tethered light source. Magnetogenetics aims to overcome these issues by manipulating neurons with magnetic stimuli. As magnetic fields can pass freely through organic tissue, it requires no surgery or tethering the animals to an energy source. In this commentary, we assess the utility of magnetogenetics based on three different approaches: magneto‐thermo‐genetics; force/torque‐based methods; and expression of the iron chaperone ISCA1. Despite some progress, many hurdles need to be overcome if magnetogenetics is to take the helm from optogenetics.

    The technology has great potential as a tool for precise and efficient activation of neurons in any species without the need for invasive surgery but many technical and biological hurdles still stand in the way of application.

    • © 2017 The Authors. Published under the terms of the CC BY 4.0 license

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Simon Nimpf, David A Keays
    Published online 14.06.2017
    • Neuroscience
  • You have access
    A microRNA‐129‐5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses
    A microRNA‐129‐5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses
    1. Marek Rajman1,
    2. Franziska Metge2,12,
    3. Roberto Fiore1,
    4. Sharof Khudayberdiev1,
    5. Ayla Aksoy‐Aksel1,13,
    6. Silvia Bicker1,
    7. Cristina Ruedell Reschke3,
    8. Rana Raoof3,
    9. Gary P Brennan3,
    10. Norman Delanty4,
    11. Michael A Farrell4,
    12. Donncha F O'Brien4,
    13. Sebastian Bauer5,6,
    14. Braxton Norwood5,6,
    15. Morten T Veno7,
    16. Marcus Krüger8,9,10,
    17. Thomas Braun11,
    18. Jørgen Kjems7,
    19. Felix Rosenow5,6,
    20. David C Henshall3,
    21. Christoph Dieterich2 and
    22. Gerhard Schratt (schratt{at}staff.uni-marburg.de)*,1
    1. 1Biochemisch‐Pharmakologisches Centrum, Institut für Physiologische Chemie, Philipps‐Universität Marburg, Marburg, Germany
    2. 2Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, Department of Internal Medicine III, German Center for Cardiovascular Research (DZHK), University Hospital Heidelberg, Heidelberg, Germany
    3. 3Physiology & Medical Physics Department, Royal College of Surgeons in Ireland, Dublin, Ireland
    4. 4Beaumont Hospital, Dublin, Ireland
    5. 5Epilepsiezentrum Frankfurt Rhein‐Main, Neurozentrum, Goethe‐Universität Frankfurt, Frankfurt, Germany
    6. 6Epilepsiezentrum Hessen – Marburg, Philipps‐Universität Marburg, Marburg, Germany
    7. 7Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark
    8. 8Institute for Genetics, University of Cologne, Cologne, Germany
    9. 9Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany
    10. 10Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
    11. 11Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    12. 12Present Address: Max Planck Institute for Biology of Ageing, Cologne, Germany
    13. 13Present Address: Hertie Institute for Clinical Brain Research & Centre for Integrative Neuroscience, Tübingen, Germany
    1. ↵*Corresponding author. Tel: +49 6421 2865020; E‐mail: schratt{at}staff.uni-marburg.de

    Combining miRNA and mRNA profiling with proteomics reveals roles for miR‐129‐5p and the RNA‐binding protein Rbfox in excitatory synapse function and epileptic seizure.

    Synopsis

    A systematic approach using small RNA and mRNA profiling in combination with proteomics is used to delineate post‐transcriptional regulatory pathways involved in synaptic scaling. This led to the identification of a pathway consisting of the miRNA miR‐129‐5p and the RNA‐binding protein Rbfox that controls excitatory synapse function in neurons and epileptic seizure activity in the brain.

    • 8 microRNAs, including miR‐129‐5p, are upregulated during homeostatic synaptic downscaling in hippocampal neurons.

    • miR‐129‐5p inhibition blocks synaptic downscaling in vitro and kainic acid‐induced epileptic seizures in vivo.

    • A combination of transcriptomics, proteomics and bioinformatics was used to identify miR‐129‐5p target mRNAs, including Atp2b4, Dcx and Rbfox1/3.

    • Activity‐dependent downregulation of Rbfox1 by miR‐129‐5p is required for the repression of synaptic genes during homeostatic synaptic downscaling.

    • epilepsy
    • homeostatic plasticity
    • microRNA
    • RNA‐binding protein
    • synaptic scaling

    The EMBO Journal (2017) 36: 1770–1787

    • Received September 16, 2016.
    • Revision received April 5, 2017.
    • Accepted April 7, 2017.
    • © 2017 The Authors
    Marek Rajman, Franziska Metge, Roberto Fiore, Sharof Khudayberdiev, Ayla Aksoy‐Aksel, Silvia Bicker, Cristina Ruedell Reschke, Rana Raoof, Gary P Brennan, Norman Delanty, Michael A Farrell, Donncha F O'Brien, Sebastian Bauer, Braxton Norwood, Morten T Veno, Marcus Krüger, Thomas Braun, Jørgen Kjems, Felix Rosenow, David C Henshall, Christoph Dieterich, Gerhard Schratt
    Published online 14.06.2017
    • Neuroscience
    • RNA Biology
  • You have access
    An activated Q‐SNARE/SM protein complex as a possible intermediate in SNARE assembly
    An activated Q‐SNARE/SM protein complex as a possible intermediate in SNARE assembly
    1. Shrutee Jakhanwal1,
    2. Chung‐Tien Lee2,3,
    3. Henning Urlaub2,3 and
    4. Reinhard Jahn (rjahn{at}gwdg.de)*,1
    1. 1Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    2. 2Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    3. 3Bioanalytics Group, Institute for Clinical Chemistry, University Medical Center, Göttingen, Germany
    1. ↵*Corresponding author. Tel: +49 551 201 1635; E‐mail: rjahn{at}gwdg.de

    The ternary complex syntaxin1, SNAP25a and Munc18‐1 acts as an intermediate in the SNARE assembly pathway by functioning as an acceptor for synaptobrevin/VAMP‐2.

    Synopsis

    The ternary complex syntaxin1, SNAP25a and Munc18‐1 acts as an intermediate in the SNARE assembly pathway by functioning as an acceptor for synaptobrevin/VAMP‐2.

    • Syntaxin1:SNAP25:Munc18‐1 complex acts as an efficient acceptor complex for synaptobrevin‐binding.

    • Synaptobrevin binding to this complex leads to major structural rearrangements, with Munc18‐1 being tethered to the N‐terminus of syntaxin1 in a fully‐zippered SNARE complex.

    • Syntaxin1:SNAP25:Munc18‐1 complex is resistant to disassembly by NSF‐αSNAP.

    • A full‐length synaptobrevin fragment is required to efficiently bind to the syntaxin1:SNAP25:Munc18‐1 complex.

    • intermediates
    • Munc18
    • NSF
    • SM‐protein
    • SNARE

    The EMBO Journal (2017) 36: 1788–1802

    • Received December 8, 2016.
    • Revision received March 23, 2017.
    • Accepted March 24, 2017.
    • © 2017 The Authors
    Shrutee Jakhanwal, Chung‐Tien Lee, Henning Urlaub, Reinhard Jahn
    Published online 14.06.2017
    • Membrane & Intracellular Transport
    • Neuroscience
  • You have access
    Programmed mitophagy is essential for the glycolytic switch during cell differentiation
    Programmed mitophagy is essential for the glycolytic switch during cell differentiation
    1. Lorena Esteban‐Martínez1,
    2. Elena Sierra‐Filardi1,
    3. Rebecca S McGreal2,
    4. María Salazar‐Roa3,
    5. Guillermo Mariño4,
    6. Esther Seco1,
    7. Sylvère Durand5,
    8. David Enot5,
    9. Osvaldo Graña6,
    10. Marcos Malumbres3,
    11. Ales Cvekl2,
    12. Ana María Cuervo7,
    13. Guido Kroemer5,8,9,10,11,12,13 and
    14. Patricia Boya (patricia.boya{at}csic.es)*,1
    1. 1Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
    2. 2Departments of Genetics, Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, USA
    3. 3Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    4. 4Departamento de Biología Fundamental, Universidad de Oviedo Fundación para la Investigación Sanitaria del Principado de Asturias (FINBA), Oviedo, Spain
    5. 5Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif, France
    6. 6Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    7. 7Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
    8. 8Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers, Paris, France
    9. 9INSERM, U1138, Paris, France
    10. 10Université Paris Descartes Sorbonne Paris Cité, Paris, France
    11. 11Université Pierre et Marie Curie, Paris, France
    12. 12Pôle de Biologie, Hôpital Européen Georges Pompidou AP‐HP, Paris, France
    13. 13Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
    1. ↵*Corresponding author. Tel: +34 91 8373112 Ext 4369; E‐mail: patricia.boya{at}csic.es

    Retinal ganglion cell differentiation and M1 macrophage polarization depend on metabolic reprogramming towards glycolysis, which is triggered by hypoxia‐induced autophagic degradation of mitochondria (mitophagy).

    Synopsis

    Retinal ganglion cell differentiation and M1 macrophage polarization depend on metabolic reprogramming towards glycolysis, which is triggered by hypoxia‐induced autophagic degradation of mitochondria (mitophagy).

    • Programmed mitophagy eliminates mitochondria during mouse retinal development.

    • Hypoxia‐induces NIX‐dependent mitophagy.

    • Mitophagy allows for a glycolytic shift required for retinal ganglion cell differentiation.

    • Mitophagy also regulates metabolic reprogramming during M1 macrophage polarization.

    • BNIP3L/NIX
    • hypoxia
    • macrophages
    • metabolic reprogramming
    • retinal ganglion cells

    The EMBO Journal (2017) 36: 1688–1706

    • Received October 21, 2016.
    • Revision received March 24, 2017.
    • Accepted March 27, 2017.
    • © 2017 The Authors
    Lorena Esteban‐Martínez, Elena Sierra‐Filardi, Rebecca S McGreal, María Salazar‐Roa, Guillermo Mariño, Esther Seco, Sylvère Durand, David Enot, Osvaldo Graña, Marcos Malumbres, Ales Cvekl, Ana María Cuervo, Guido Kroemer, Patricia Boya
    Published online 14.06.2017
    • Autophagy & Cell Death
    • Metabolism
    • Neuroscience
  • You have access
    Brain metabolism in health, aging, and neurodegeneration
    Brain metabolism in health, aging, and neurodegeneration
    1. Simonetta Camandola (camandolasi{at}mail.nih.gov)*,1 and
    2. Mark P Mattson (mark.mattson{at}nih.gov)*,1,2
    1. 1Laboratory of Neuroscience, National Institute on Aging, Baltimore, MD, USA
    2. 2Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    1. ↵* Corresponding author. Tel: +1 410 558 8617; E‐mail: camandolasi{at}mail.nih.gov
      Corresponding author. Tel: +1 410 558 8463; E‐mail: mark.mattson{at}nih.gov

    As part of our metabolism focus, this review provides an overview of cellular and molecular mechanisms that regulate brain energy metabolism and how such mechanisms are altered during aging and disease.

    • aging
    • brain energetics
    • ketone bodies
    • metabolism

    The EMBO Journal (2017) 36: 1474–1492

    • Received September 28, 2016.
    • Revision received January 29, 2017.
    • Accepted April 4, 2017.
    • Published 2017. This article is a U.S. Government work and is in the public domain in the USA
    Simonetta Camandola, Mark P Mattson
    Published online 01.06.2017
    • Metabolism
    • Neuroscience
  • You have access
    let‐7 regulates radial migration of new‐born neurons through positive regulation of autophagy
    let‐7 regulates radial migration of new‐born neurons through positive regulation of autophagy
    1. Rebecca Petri1,
    2. Karolina Pircs1,
    3. Marie E Jönsson1,
    4. Malin Åkerblom1,
    5. Per Ludvik Brattås1,
    6. Thies Klussendorf1 and
    7. Johan Jakobsson (johan.jakobsson{at}med.lu.se)*,1
    1. 1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden
    1. ↵*Corresponding author. Tel: +46 46 2224225; Fax: +46 46 2220559; E‐mail: johan.jakobsson{at}med.lu.se

    Adult neurogenesis requires interneurons to migrate and integrate in the olfactory bulb in a process that depends on let‐7‐dependent control of autophagy.

    Synopsis

    The highly expressed let‐7 family is crucial for radial migration of adult new‐born neurons in the olfactory bulb. The molecular mechanisms underlying this process include the positive regulation of neuronal autophagy.

    • let‐7 is highly expressed in new‐born olfactory bulb neurons.

    • Knockdown of let‐7 impairs radial migration.

    • let‐7 acts through positive regulation of autophagy.

    • Activation of autophagy restores let‐7‐impaired migration.

    • adult neurogenesis
    • Argonaute
    • microRNA
    • olfactory bulb
    • RISC

    The EMBO Journal (2017) 36: 1379–1391

    • Received July 12, 2016.
    • Revision received February 23, 2017.
    • Accepted March 1, 2017.
    • © 2017 The Authors
    Rebecca Petri, Karolina Pircs, Marie E Jönsson, Malin Åkerblom, Per Ludvik Brattås, Thies Klussendorf, Johan Jakobsson
    Published online 15.05.2017
    • Development & Differentiation
    • Neuroscience
  • You have access
    The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals
    The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals
    1. Roeland Vanhauwaert1,2,
    2. Sabine Kuenen1,2,
    3. Roy Masius3,
    4. Adekunle Bademosi4,
    5. Julia Manetsberger1,2,
    6. Nils Schoovaerts1,2,
    7. Laura Bounti1,2,
    8. Serguei Gontcharenko1,2,
    9. Jef Swerts1,2,
    10. Sven Vilain1,2,
    11. Marina Picillo5,
    12. Paolo Barone5,
    13. Shashini T Munshi6,
    14. Femke MS de Vrij6,
    15. Steven A Kushner6,
    16. Natalia V Gounko1,2,7,
    17. Wim Mandemakers3,
    18. Vincenzo Bonifati3,
    19. Frederic A Meunier4,
    20. Sandra‐Fausia Soukup (sandra.soukup{at}cme.vib-kuleuven.be)*,1,2 and
    21. Patrik Verstreken (patrik.verstreken{at}cme.vib-kuleuven.be)*,1,2
    1. 1VIB Center for Brain & Disease Research, Leuven, Belgium
    2. 2Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), KU Leuven, Leuven, Belgium
    3. 3Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
    4. 4Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia
    5. 5Department of Medicine and Surgery, Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Salerno, Italy
    6. 6Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands
    7. 7Electron Microscopy Platform, VIB Bio‐Imaging Core, Leuven, Belgium
    1. ↵* Corresponding author. Tel: +32 1637 7035; E‐mail: sandra.soukup{at}cme.vib-kuleuven.be
      Corresponding author. Tel: +32 1633 0018; E‐mail: patrik.verstreken{at}cme.vib-kuleuven.be

    The Parkinson's disease‐associated lipid phosphatase synaptojanin promotes synaptic autophagosome formation, a function that is impaired by pathogenic mutations.

    Synopsis

    Parkinson's disease‐related human synaptojanin 1 (SYNJ1) or Drosophila synaptojanin (Synj) SAC1 function drives autophagosome biogenesis within synapses by dephosphorylating PI(3)P/PI(3,5)P2, releasing WIPI2/Atg18a from immature autophagosomes, independent from Synj function in endocytosis.

    • Parkinson's disease related synaptojanin RQ SAC1 mutation does not affect synaptic vesicle endocytosis at fly excitatory glutamatergic neurons and photoreceptors.

    • Synaptojanin is required for autophagosome formation in presynaptic terminals, analogous to synaptic vesicle uncoating by synaptojanin.

    • The PI(3)P/PI(3,5)P2‐binding protein, WIPI2/Atg18a accumulates in Synj mutant flies and SYNJ1 R258Q patient‐derived human induced neurons.

    • Synaptojanin regulates Atg18a mobility at autophagosomal membranes.

    • Synaptojanin RQ knock‐in flies show neurodegeneration.

    • correlative light and electron microscopy
    • induced pluripotent stem cells
    • Parkinson's disease
    • single‐molecule tracking
    • synapse

    The EMBO Journal (2017) 36: 1392–1411

    • Received September 22, 2016.
    • Revision received February 25, 2017.
    • Accepted March 1, 2017.
    • © 2017 The Authors
    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
    Published online 15.05.2017
    • Autophagy & Cell Death
    • Neuroscience

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