title: Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.
abstract: Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER-endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell-derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations inspastin,strumpellin, orREEP1cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER-endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.|Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: Rachel
authors.identifier: 0000-0002-2446-8455
authors.initials: R
authors.lastname: Allison
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.|Department of Clinical Biochemistry, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: James R
authors.identifier: 0000-0001-7903-8199
authors.initials: JR
authors.lastname: Edgar
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.|Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: Guy
authors.identifier: 0000-0001-8623-9239
authors.initials: G
authors.lastname: Pearson
authors.affiliation: Interdisciplinary Center for Clinical Research (IZKF) Junior Research Group III and Federal Ministry of Education and Research (BMBF) Research Group Neuroscience, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.
authors.forename: Tania
authors.identifier: 0000-0003-4922-7719
authors.initials: T
authors.lastname: Rizo
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.|Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Newton
authors.affiliation: Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Sven
authors.identifier: 0000-0003-1118-8726
authors.initials: S
authors.lastname: Günther
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: Fiamma
authors.identifier: 0000-0001-5625-5537
authors.initials: F
authors.lastname: Berner
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.|Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: Jennifer
authors.identifier: 0000-0002-9779-8009
authors.initials: J
authors.lastname: Hague
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.|Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Connell
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.
authors.forename: Jürgen
authors.identifier: 0000-0003-0630-9204
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147.
authors.forename: Jennifer
authors.identifier: 0000-0002-8601-3501
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.affiliation: Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Christian
authors.identifier: 0000-0001-7061-2895
authors.initials: C
authors.lastname: Beetz
authors.affiliation: Interdisciplinary Center for Clinical Research (IZKF) Junior Research Group III and Federal Ministry of Education and Research (BMBF) Research Group Neuroscience, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.|Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK ealr4@cam.ac.uk.|Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.
authors.forename: Evan
authors.identifier: 0000-0003-1623-7304
authors.initials: E
authors.lastname: Reid
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015419:Spastic Paraplegia, Hereditary / Q000378:metabolism*