C9orf72 arginine-rich dipeptide repeat proteins disrupt karyopherin-mediated nuclear import.
Elife
; 92020 03 02.
Article
em En
| MEDLINE
| ID: mdl-32119645
ABSTRACT
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 ß 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 ß, disrupt its cargo loading, and inhibit nuclear import of importin ß, importin α/ß, 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Arginina
/
Carioferinas
/
Dipeptídeos
/
Proteína C9orf72
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Elife
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos