Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD

Disruption of the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) have been implicated in the pathogenesis of neurodegenerative diseases. A GGGGCC hexanucleotide repeat expansion (HRE) in an intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and fron-totemporal dementia, but the mechanism by which the HRE disrupts NCT is incompletely understood. We find that expression of GGGGCC repeats in Drosophila neurons induces proteasome-mediated degradation of select nucleoporins of the NPC. This process requires the Vps4 ATPase and the endosomal-sorting com-plex required for transport complex-III (ESCRT-III), as knockdown of ESCRT-III/Vps4 genes rescues nucleo-porin levels, normalizes NCT, and suppresses GGGGCC-mediated neurodegeneration. GGGGCC expression upregulates nuclear ESCRT-III/Vps4 expression, and expansion microscopy demonstrates that the nucleo-porins are translocated into the cytoplasm before undergoing proteasome-mediated degradation. These findings demonstrate a mechanism for nucleoporin degradation and NPC dysfunction in neurodegenerative disease.

Automated summary

This study found that expression of GGGGCC repeats in Drosophila neurons leads to degradation of nucleoporins and this process is mediated by the Vps4 ATPase and the ESCRT-III complex, revealing a mechanism for nuclear pore complex dysfunction in neurodegenerative diseases.