부산대학교 도서관

Disruption of nucleocytoplasmic transport is increasingly implicated in the pathogenesis of neurodegenerative diseases, including ALS caused by a C9orf72 hexanucleotide repeat expansion. However, the mechanism(s) remain unclear. Karyopherins, including importin [beta] and its cargo adaptors, have been shown to co-precipitate with the C9orf72 arginine-containing dipeptide repeat proteins (R-DPRs), poly-glycine arginine (GR) and poly-proline arginine (PR), and are protective in genetic modifier screens. Here, we show that R-DPRs interact with importin [beta], disrupt its cargo loading, and inhibit nuclear import of importin [beta], importin [alpha]/[beta], and transportin cargoes in permeabilized mouse neurons and HeLa cells, in a manner that can be rescued by RNA. Although R-DPRs induce widespread protein aggregation in this in vitro system, transport disruption is not due to nucleocytoplasmic transport protein sequestration, nor blockade of the phenylalanine-glycine (FG)-rich nuclear pore complex. Our results support a model in which R-DPRs interfere with cargo loading on karyopherins.
Byline: Lindsey R Hayes, Lauren Duan, Kelly Bowen, Petr Kalab, Jeffrey D Rothstein Introduction A GGGGCC hexanucleotide repeat expansion (HRE) in C9orf72 is the most common known cause of amyotrophic [...]