{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:50:19Z","timestamp":1790776219390,"version":"4.1.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"CureSPG47 Inc."},{"name":"Spastic Paraplegia Foundation"},{"DOI":"10.13039\/100005627","name":"Thrasher Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005627","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of W\u00fcrzburg Graduate School of Life Sciences Scholarship"},{"DOI":"10.13039\/501100004350","name":"German National Academic Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012990","name":"University of Siena","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012990","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["1764\/2\u20131"],"award-info":[{"award-number":["1764\/2\u20131"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004189","name":"Max Planck Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004189","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust Principal Research Fellowship","award":["086598"],"award-info":[{"award-number":["086598"]}]},{"DOI":"10.13039\/100011495","name":"Massachusetts Life Sciences Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011495","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007857","name":"Intellectual and Developmental Disabilities Research Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1U54HD090255"],"award-info":[{"award-number":["1U54HD090255"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <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\u20135-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>","DOI":"10.1093\/hmg\/ddz310","type":"journal-article","created":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T07:10:18Z","timestamp":1576653018000},"page":"320-334","source":"Crossref","is-referenced-by-count":78,"title":["Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking"],"prefix":"10.1093","volume":"29","author":[{"given":"Robert","family":"Behne","sequence":"first","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Neurology, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Teinert","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Wimmer","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris, 56018 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra K","family":"Davies","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK"},{"name":"Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M","family":"Scarrott","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Brechmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy Pin-Fang","family":"Chen","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth D","family":"Buttermore","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Barrett","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Dwyer","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Chen","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Hirst","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Wiesener","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Friedrich-Alexander Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devorah","family":"Segal","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York City, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Martinuzzi","sequence":"additional","affiliation":[{"name":"Scientific Institute, IRCCS E. Medea, Unit\u00e0 Operativa Conegliano, 31015 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia T","family":"Duarte","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Centro Hospitalar de Lisboa Central, 1169-050 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T","family":"Bennett","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bourinaris","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agathe","family":"Roubertie","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, CHU Montpellier, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo M","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris, 56018 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Robinson","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mimoun","family":"Azzouz","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan O","family":"Lipton","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg H H","family":"Borner","sequence":"additional","affiliation":[{"name":"Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. 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