450-VCP Drive Pathogenic Nuclear Pore Complex Degradation

Paper Talk · Jan 30, 2026 · 16m

This research identifies Valosin-containing protein (VCP) as a critical regulator of nuclear pore complex (NPC) integrity in neurons and muscle cells. Under healthy conditions, VCP uses the Ufd1-Npl4 cofactor to remove and degrade specific nucleoporins, maintaining cellular balance. However, pathogenic VCP mutations cause a toxic gain-of-function where the protein excessively strips these essential components from the nuclear envelope. This aggressive degradation leads to structural NPC defects, failing nucleocytoplasmic transport, and the mislocalization of the protein TDP-43. Consequently…