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.