{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T12:14:51Z","timestamp":1788178491197,"version":"build-2803163510"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2022,3,26]],"date-time":"2022-03-26T00:00:00Z","timestamp":1648252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,23]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1\u201386 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A) and the reticulon-like, microtubule-binding protein REEP1 (REEP1; SPG31). These proteins bind one another and function in shaping the tubular endoplasmic reticulum (ER) network. Typically, mouse models of HSPs have mild, later onset phenotypes, possibly reflecting far shorter lengths of their corticospinal axons relative to humans. Here, we have generated a robust, double mutant mouse model of HSP in which atlastin-1 is genetically modified with a K80A knock-in (KI) missense change that abolishes its GTPase activity, whereas its binding partner Reep1 is knocked out. Atl1KI\/KI\/Reep1\u2212\/\u2212 mice exhibit early onset and rapidly progressive declines in several motor function tests. Also, ER in mutant corticospinal axons dramatically expands transversely and periodically in a mutation dosage-dependent manner to create a ladder-like appearance, on the basis of reconstructions of focused ion beam-scanning electron microscopy datasets using machine learning-based auto-segmentation. In lockstep with changes in ER morphology, axonal mitochondria are fragmented and proportions of hypophosphorylated neurofilament H and M subunits are dramatically increased in Atl1KI\/KI\/Reep1\u2212\/\u2212 spinal cord. Co-occurrence of these findings links ER morphology changes to alterations in mitochondrial morphology and cytoskeletal organization. Atl1KI\/KI\/Reep1\u2212\/\u2212 mice represent an early onset rodent HSP model with robust behavioral and cellular readouts for testing novel therapies.<\/jats:p>","DOI":"10.1093\/hmg\/ddac072","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T20:11:15Z","timestamp":1647979875000},"page":"2779-2795","source":"Crossref","is-referenced-by-count":33,"title":["Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons"],"prefix":"10.1093","volume":"31","author":[{"given":"Peng-Peng","family":"Zhu","sequence":"first","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Fang","family":"Hung","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"MassGeneral Institute for Neurodegenerative Disease , Charlestown, MA 02129, USA"},{"name":"Department of Neurology , Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Batchenkova","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon","family":"Nixon-Abell","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA"},{"name":"Cambridge Institute for Medical Research , Cambridge CB2 0XY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Henderson","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research , Cambridge CB2 0XY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengli","family":"Zheng","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"MassGeneral Institute for Neurodegenerative Disease , Charlestown, MA 02129, USA"},{"name":"Department of Neurology , Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Renvois\u00e9","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Pang","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Shan","family":"Xu","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Saalfeld","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Funke","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Xie","sequence":"additional","affiliation":[{"name":"Synaptic Function Section , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Svara","sequence":"additional","affiliation":[{"name":"ariadne.ai ag , CH-6033 Buchrain, Switzerland"},{"name":"Research Center Caesar , D-53175 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald F","family":"Hess","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1261-9655","authenticated-orcid":false,"given":"Craig","family":"Blackstone","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"MassGeneral Institute for Neurodegenerative Disease , Charlestown, MA 02129, USA"},{"name":"Department of Neurology , Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,26]]},"reference":[{"key":"2022082420180591100_ref1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11910-019-0930-2","article-title":"Update on the genetics of spastic paraplegias","volume":"19","author":"Boutry","year":"2019","journal-title":"Curr. 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