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
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- Julian Teinert
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Miriam Wimmer
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Angelica D’Amore
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Alexandra K Davies
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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- Joseph M Scarrott
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK
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- Kathrin Eberhardt
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Barbara Brechmann
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Ivy Pin-Fang Chen
- Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Elizabeth D Buttermore
- Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Lee Barrett
- Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Sean Dwyer
- Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Teresa Chen
- Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Jennifer Hirst
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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- Antje Wiesener
- Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
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- Devorah Segal
- Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York City, NY 10021, USA
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- Andrea Martinuzzi
- Scientific Institute, IRCCS E. Medea, Unità Operativa Conegliano, 31015 Treviso, Italy
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- Sofia T Duarte
- Department of Pediatric Neurology, Centro Hospitalar de Lisboa Central, 1169-050 Lisbon, Portugal
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- James T Bennett
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
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- Thomas Bourinaris
- Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK
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- Henry Houlden
- Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK
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- Agathe Roubertie
- Pediatric Neurology, CHU Montpellier, 34295 Montpellier, France
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- Filippo M Santorelli
- Molecular Medicine, IRCCS Fondazione Stella Maris, 56018 Pisa, Italy
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- Margaret Robinson
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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- Mimoun Azzouz
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK
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- Jonathan O Lipton
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Georg H H Borner
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
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- Mustafa Sahin
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Darius Ebrahimi-Fakhari
- Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
説明
<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>
収録刊行物
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- Human Molecular Genetics
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Human Molecular Genetics 29 (2), 320-334, 2020-01-09
Oxford University Press (OUP)
