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journal article·2026-01Open access

REEP1 Accumulation Disrupts ER Integrity and Drives Spinal Motoneuron Degeneration in Distal Hereditary Motor Neuropathy

Andrea Bock, Mona Schurig, Miles Willoughby, Andrea Mirecki, Eric Seemann, Kateryna Lohachova, Istvan Katona, Sonnhild Mittag, Lutz Liebmann, Patricia Franzka, Mehdi Heidari Horestani, Mukhran Khundadze, Thorsten Mosler, Timothy Louie, Marianne de Visser, Marian A. J. Weterman, Michael Kiehntopf, Christian Beetz, Sandor Nietzsche, Otmar Huber, Joachim Weis, Michael M. Kessels, Ramachandra M. Bhaskara, Britta Qualmann, Ivan Đikić, Christian A. Hübner

Advanced Science· Volume 13· Issue 2
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Source abstract

Abstract

Abstract REEP1 contributes to the shaping of the endoplasmic reticulum (ER) through conserved transmembrane hairpins and a long C‐terminal amphipathic helix. REEP1 loss‐of‐function causes hereditary spastic paraplegia due to degeneration of cortical motoneuron axons. Patients with deletion of REEP1 exon5 (Δexon5), 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 REEP1 knockout mice exhibit simplified ER structures in cortical motoneurons. Here, we show that these neurons are progressively lost while spinal motoneurons remain intact. Conversely, Δexon5 knockin (KI) mice lose spinal motoneurons preceded by ER fragmentation, whereas cortical motoneurons remain intact. Mechanistically, REEP1 undergoes ubiquitination and proteasomal degradation, a process compromised in the Δexon5 variant due to impaired ubiquitination, which thus accumulates in peripheral nerves. Proteomic analysis identifies HUWE1 as the E3 ligase responsible for REEP1 turnover. Modeling and liposome shaping assays reveal that the Δexon5 variant retains its capacity to induce membrane curvature. Consistently, other REEP1 variants associated with dHMN also show compromised ubiquitination and preserved transmembrane hairpins. Therefore, it is proposed that accumulation of shaping‐competent REEP1 variants in the ER drives ER fragmentation and spinal motoneuron degeneration in dHMN.
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Research context

OpenAlex topics: Hereditary Neurological Disorders · Neurogenetic and Muscular Disorders Research · Cellular transport and secretion

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Institute of Human Genetics Jena University Hospital Friedrich Schiller University Am Klinikum 1 07747 Jena Germany

Institute of Biochemistry II Goethe University School of Medicine Theodor‐Stern‐Kai 7 60590 Frankfurt am Main Germany

Institute for Biochemistry I Jena University Hospital Friedrich‐Schiller‐University Nonnenplan 2‐4 07743 Jena Germany

Buchmann Institute for Molecular Life Sciences Goethe University Frankfurt Max‐von‐Laue Straße 15 60438 Frankfurt am Main Germany

Institute of Neuropathology RWTH Aachen University Hospital Pauwelsstr. 30 52074 Aachen Germany

Department of Neurology Houston Methodist Research Institute Houston Texas USA

Institute for Biochemistry II Jena University Hospital Friedrich‐Schiller‐University Nonnenplan 2‐4 07743 Jena Germany

Swift Institute – Vein and Neurology 10381 Double R. Blvd. Reno NV 89521 USA

Department of Neurology Academic Medical Center Amsterdam The Netherlands

Department of Genome Analysis/Clinical Genetics Amsterdam University Medical Center Location Academic Medical Center Amsterdam 1081 BT The Netherlands

Dept Clinical Genetics LUMC Leiden 2300RC The Netherlands

Institute for Clinical and Laboratory Medicine Jena University Hospital Friedrich Schiller University Am Klinikum 1 07747 Jena Germany

Center for Electron Microscopy Jena University Hospital Ziegelmühlenweg 1 07743 Jena Germany

Center for Rare Diseases Friedrich Schiller University Am Klinikum1 07747 Jena Germany

Funding

Bundesministerium für Bildung und Forschung · Thüringer Aufbaubank · European Research Council

References (69)

Show source-provided references
1. 10.1242/jcs.25198310.1242/jcs.251983 ↗
2. 10.1007/s00018-015-2052-610.1007/s00018-015-2052-6 ↗
3. 10.3389/fncel.2020.55646110.3389/fncel.2020.556461 ↗
4. 10.1002/dneu.2256010.1002/dneu.22560 ↗
5. 10.3389/fnins.2020.0004810.3389/fnins.2020.00048 ↗
6. 10.1093/brain/awu28710.1093/brain/awu287 ↗
7. 10.1007/s00415005050310.1007/s004150050503 ↗
8. 10.1086/50536110.1086/505361 ↗
9. 10.1016/j.ajhg.2012.05.00710.1016/j.ajhg.2012.05.007 ↗
10. 10.1172/JCI4097910.1172/JCI40979 ↗
11. 10.1016/j.cell.2005.11.04710.1016/j.cell.2005.11.047 ↗
12. 10.1038/s41467-019-10345-310.1038/s41467-019-10345-3 ↗
13. 10.1038/s41467-020-20625-y10.1038/s41467-020-20625-y ↗
14. Renvoisé B. · Hum. Mol. Genet. · 2016 · 25 · 5111
15. 10.1016/j.devcel.2013.06.01610.1016/j.devcel.2013.06.016 ↗
16. 10.1083/jcb.20210104910.1083/jcb.202101049 ↗
17. 10.1080/15548627.2023.221402910.1080/15548627.2023.2214029 ↗
18. 10.1038/s41467-023-40530-410.1038/s41467-023-40530-4 ↗
19. 10.1371/journal.pbio.300237210.1371/journal.pbio.3002372 ↗
20. 10.1038/s41467-024-52901-610.1038/s41467-024-52901-6 ↗
21. 10.1016/j.cell.2009.05.02510.1016/j.cell.2009.05.025 ↗
22. 10.1038/nature0828010.1038/nature08280 ↗
23. 10.1172/JCI6566510.1172/JCI65665 ↗
24. 10.1073/pnas.132161411110.1073/pnas.1321614111 ↗
25. 10.1093/nar/gku29110.1093/nar/gku291 ↗
26. 10.1093/bioinformatics/btp03310.1093/bioinformatics/btp033 ↗
27. 10.1038/s41586-021-03819-210.1038/s41586-021-03819-2 ↗
28. 10.1093/bioinformatics/btn39210.1093/bioinformatics/btn392 ↗
29. 10.1021/jp071097f10.1021/jp071097f ↗
30. 10.1021/ct700324x10.1021/ct700324x ↗
31. 10.1002/bip.36022121110.1002/bip.360221211 ↗
32. 10.1021/acs.jctc.0c0106410.1021/acs.jctc.0c01064 ↗
33. 10.1073/pnas.240807112110.1073/pnas.2408071121 ↗
34. 10.1093/nar/gkr70310.1093/nar/gkr703 ↗
35. 10.1021/acs.jctc.5b0020910.1021/acs.jctc.5b00209 ↗
36. 10.1002/jcc.2094510.1002/jcc.20945 ↗
37. 10.1080/0026897840010120110.1080/00268978400101201 ↗
38. 10.1063/1.44733410.1063/1.447334 ↗
39. 10.1063/1.32869310.1063/1.328693 ↗
40. 10.1016/S0006-3495(00)76304-110.1016/S0006-3495(00)76304-1 ↗
41. 10.1002/(SICI)1097-0134(19990215)34:3<269::AID-PROT1>3.0.CO;2-310.1002/(SICI)1097-0134(19990215)34:3<269::AID-PROT1>3.0.CO;2-3 ↗
42. 10.1523/JNEUROSCI.3973-09.200910.1523/JNEUROSCI.3973-09.2009 ↗
43. 10.1523/JNEUROSCI.0269-11.201110.1523/JNEUROSCI.0269-11.2011 ↗
44. 10.1021/pr101065j10.1021/pr101065j ↗
45. 10.1038/nprot.2016.13610.1038/nprot.2016.136 ↗
46. 10.1038/nmeth101910.1038/nmeth1019 ↗
47. 10.1074/mcp.M113.03159110.1074/mcp.M113.031591 ↗
48. 10.1093/nar/gkae101110.1093/nar/gkae1011 ↗
49. 10.1186/1471-2105-14-12810.1186/1471-2105-14-128 ↗
50. 10.1093/nar/gkw37710.1093/nar/gkw377 ↗
51. 10.1002/cpz1.9010.1002/cpz1.90 ↗
52. 10.1073/pnas.90.18.842410.1073/pnas.90.18.8424 ↗
53. 10.1093/hmg/ddac07210.1093/hmg/ddac072 ↗
54. 10.1038/s41586-023-06090-910.1038/s41586-023-06090-9 ↗
55. 10.1371/journal.pone.017466710.1371/journal.pone.0174667 ↗
56. 10.1016/0022-510X(88)90221-310.1016/0022-510X(88)90221-3 ↗
57. 10.1002/humu.2154210.1002/humu.21542 ↗
58. 10.1186/1471-2350-9-7110.1186/1471-2350-9-71 ↗
59. 10.1038/414652a10.1038/414652a ↗
60. 10.1136/bmjopen-2015-00953710.1136/bmjopen-2015-009537 ↗
61. Juberg R. C. · Am. J. Hum. Genet. · 1980 · 32 · 714
62. 10.1016/j.cell.2004.11.02110.1016/j.cell.2004.11.021 ↗
63. 10.1038/s41418-019-0444-010.1038/s41418-019-0444-0 ↗
64. 10.1126/science.115363410.1126/science.1153634 ↗
65. 10.1074/jbc.M80098620010.1074/jbc.M800986200 ↗
66. 10.1038/nbt1210-124810.1038/nbt1210-1248 ↗
67. 10.1007/s10048-004-0191-210.1007/s10048-004-0191-2 ↗
68. 10.1001/archneur.61.12.186710.1001/archneur.61.12.1867 ↗
69. 10.1001/archneur.61.10.160010.1001/archneur.61.10.1600 ↗