PXD067700-1

PXD067700 is an original dataset announced via ProteomeXchange.

Title	REEP1 Accumulation Disrupts ER Integrity and Drives Spinal Motoneuron Degeneration in Distal Hereditary Motor Neuropathy
Description	REEP1 contributes to the shaping of the endoplasmic reticulum (ER) through conserved transmembrane hairpins (THs) and a long C-terminal amphipathic helix. Its loss-of-function causes spastic paraplegia due to degeneration of axons of cortical motoneurons projecting to spinal motoneurons. Patients with deletion of REEP1 exon5 (Δexon5), which deletes a part of its amphipathic helix, however, develop muscle atrophy due to degeneration of spinal motoneuron axons (distal hereditary motor neuropathy/dHMN). We show that Reep1 KO mice exhibit simplified ER structures and lose cortical motoneurons, while spinal motoneurons remain intact. Conversely, Δexon5 KI mice lose spinal motoneurons preceded by ER-fragmentation, whereas cortical motoneurons remain intact. Mechanistically, wild-type REEP1 undergoes ubiquitination and proteasomal degradation, a process disrupted in the Δexon5 variant due to impaired ubiquitination. As a result, the Δexon5 variant accumulates in peripheral nerves of KI mice. 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 but preserve membrane remodeling features. Therefore, we propose that accumulation of shaping-competent REEP1 variants in the ER drives ER-fragmentation and spinal motoneuron degeneration in dHMN.
HostingRepository	PRIDE
AnnounceDate	2026-01-19
AnnouncementXML	Submission_2026-01-18_16:25:12.802.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thorsten Mosler
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-25 07:40:45	ID requested
⏵ 1	2026-01-18 16:25:13	announced

Bock A, Schurig M, Willoughby M, Mirecki A, Seemann E, Lohachova K, Katona I, Mittag S, Liebmann L, Franzka P, Heidari Horestani M, Khundadze M, Mosler T, Louie T, de Visser M, Weterman MAJ, Kiehntopf M, Beetz C, Nietzsche S, Huber O, Weis J, Kessels MM, Bhaskara RM, Qualmann B, Đ, iki, ć I, H, ü, bner CA, REEP1 Accumulation Disrupts ER Integrity and Drives Spinal Motoneuron Degeneration in Distal Hereditary Motor Neuropathy. Adv Sci (Weinh), 13(2):e11483(2026) [pubmed]

10.1002/advs.202511483;

submitter keyword: REEP1, dHMN, membrane shaping, endoplasmic reticulum, ubiquitination, HSP

Christian A. Hübner
contact affiliation	Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany Center for Rare Diseases, University Hospital Jena, Friedrich Schiller University, Am Klinikum1, 07747 Jena, Germany
contact email	Christian.Huebner@med.uni-jena.de
lab head
Thorsten Mosler
contact affiliation	Goethe University Clinics Frankfurt
contact email	thorstenmosler@googlemail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067700
     1. Label: PRIDE project
     2. Name: REEP1 Accumulation Disrupts ER Integrity and Drives Spinal Motoneuron Degeneration in Distal Hereditary Motor Neuropathy