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

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.