Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking

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  • Robert Behne
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Julian Teinert
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Miriam Wimmer
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Angelica D’Amore
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Alexandra K Davies
    Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
  • Joseph M Scarrott
    Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK
  • Kathrin Eberhardt
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Barbara Brechmann
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Ivy Pin-Fang Chen
    Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Elizabeth D Buttermore
    Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Lee Barrett
    Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Sean Dwyer
    Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Teresa Chen
    Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Jennifer Hirst
    Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
  • Antje Wiesener
    Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
  • Devorah Segal
    Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York City, NY 10021, USA
  • Andrea Martinuzzi
    Scientific Institute, IRCCS E. Medea, Unità Operativa Conegliano, 31015 Treviso, Italy
  • Sofia T Duarte
    Department of Pediatric Neurology, Centro Hospitalar de Lisboa Central, 1169-050 Lisbon, Portugal
  • James T Bennett
    Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
  • Thomas Bourinaris
    Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK
  • Henry Houlden
    Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK
  • Agathe Roubertie
    Pediatric Neurology, CHU Montpellier, 34295 Montpellier, France
  • Filippo M Santorelli
    Molecular Medicine, IRCCS Fondazione Stella Maris, 56018 Pisa, Italy
  • Margaret Robinson
    Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
  • Mimoun Azzouz
    Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK
  • Jonathan O Lipton
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Georg H H Borner
    Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
  • Mustafa Sahin
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • Darius Ebrahimi-Fakhari
    Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA

Description

<jats:title>Abstract</jats:title> <jats:p>Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.</jats:p>

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