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Patients with deletion of\n                    <jats:italic>REEP1<\/jats:italic>\n                    exon5 (\u0394exon5), which deletes part of its amphipathic helix, however, develop muscle atrophy due to degeneration of spinal motoneuron axons (distal hereditary motor neuropathy\/dHMN). It is known that\n                    <jats:italic>REEP1<\/jats:italic>\n                    knockout mice exhibit simplified ER structures in cortical motoneurons. Here, we show that these neurons are progressively lost\u00a0while spinal motoneurons remain intact. Conversely, \u0394exon5 knockin (KI) mice lose spinal motoneurons preceded by ER fragmentation, whereas cortical motoneurons remain intact. Mechanistically,\n                    <jats:italic>REEP1<\/jats:italic>\n                    undergoes ubiquitination and proteasomal degradation, a process compromised in the \u0394exon5 variant due to impaired ubiquitination, which thus accumulates in peripheral nerves. Proteomic analysis identifies\n                    <jats:italic>HUWE1<\/jats:italic>\n                    as the E3 ligase responsible for\n                    <jats:italic>REEP1<\/jats:italic>\n                    turnover. Modeling and liposome shaping assays reveal that the \u0394exon5 variant retains its capacity to induce membrane curvature. Consistently, other\n                    <jats:italic>REEP1<\/jats:italic>\n                    variants associated with dHMN also show compromised ubiquitination and preserved transmembrane hairpins. Therefore, it is proposed that accumulation of shaping\u2010competent\n                    <jats:italic>REEP1<\/jats:italic>\n                    variants in the ER drives ER fragmentation and spinal motoneuron degeneration in dHMN.\n                  <\/jats:p>","DOI":"10.1002\/advs.202511483","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T10:31:01Z","timestamp":1763721061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>REEP1<\/i>\n                    Accumulation Disrupts ER Integrity and Drives Spinal Motoneuron Degeneration in Distal Hereditary Motor Neuropathy"],"prefix":"10.1002","volume":"13","author":[{"given":"Andrea","family":"Bock","sequence":"first","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mona","family":"Schurig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miles","family":"Willoughby","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry II Goethe University School of Medicine  Theodor\u2010Stern\u2010Kai 7 60590 Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Mirecki","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Seemann","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry I Jena University Hospital Friedrich\u2010Schiller\u2010University  Nonnenplan 2\u20104 07743 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kateryna","family":"Lohachova","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry II Goethe University School of Medicine  Theodor\u2010Stern\u2010Kai 7 60590 Frankfurt am Main Germany"},{"name":"Buchmann Institute for Molecular Life Sciences Goethe University Frankfurt  Max\u2010von\u2010Laue Stra\u00dfe 15 60438 Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istvan","family":"Katona","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Pauwelsstr. 30 52074 Aachen Germany"},{"name":"Department of Neurology Houston Methodist Research Institute  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonnhild","family":"Mittag","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry II Jena University Hospital Friedrich\u2010Schiller\u2010University  Nonnenplan 2\u20104 07743 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lutz","family":"Liebmann","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Franzka","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehdi","family":"Heidari Horestani","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mukhran","family":"Khundadze","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Jena University Hospital Friedrich Schiller University  Am Klinikum 1 07747 Jena Germany"},{"name":"Department of Neurology Houston Methodist Research Institute  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorsten","family":"Mosler","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry II Goethe University School of Medicine  Theodor\u2010Stern\u2010Kai 7 60590 Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Louie","sequence":"additional","affiliation":[{"name":"Swift Institute \u2013 Vein and Neurology  10381 Double R. 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