A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels

The GJA1^R148Q variant, although non-neurological in isolation, acts as a disease modifier that precipitates SPG4 by exacerbating SPASTIN haploinsufficiency through destabilization of VCPIP1, positioning GJA1-VCPIP1-SPASTIN signaling as a potential therapeutic axis for SPG4 treatment. © 2026 International Parkinson and Movement Disorder Society.