Please use this identifier to cite or link to this item: http://hdl.handle.net/2067/52683
Title: C9orf72 Toxic Species Affect ArfGAP-1 Function
Authors: Rossi, Simona
Di Salvio, Michela
Balì, Marilisa
De Simone, Assia
Apolloni, Savina
D'Ambrosi, Nadia
Arisi, Ivan
Cipressa, Francesca 
Cozzolino, Mauro
Cestra, Gianluca
Journal: CELLS 
Issue Date: 2023
Abstract: 
Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs. We previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in the cell nuclei. To further characterize the process, we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS RNA repeats. Interestingly, pathway analysis showed that the mRNAs involved in membrane trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicated that C9orf72 toxic species affect the membrane trafficking route regulated by ADP-Ribosylation Factor 1 GTPase Activating Protein (ArfGAP-1), which exerts its GTPase-activating function on the small GTPase ADP-ribosylation factor 1 to dissociate coat proteins from Golgi-derived vesicles. We demonstrate that the function of ArfGAP-1 is specifically affected by expanded C9orf72 RNA repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), indicating the retrograde Golgi-to-ER vesicle-mediated transport as a target of C9orf72 toxicity.
URI: http://hdl.handle.net/2067/52683
ISSN: 2073-4409
DOI: 10.3390/cells12152007
Appears in Collections:A1. Articolo in rivista

Files in This Item:
File Description SizeFormat Existing users please
2. c9orf.pdf878.5 kBAdobe PDF    Request a copy
Show full item record

SCOPUSTM   
Citations

1
checked on Jan 31, 2025

Page view(s)

6
checked on Feb 5, 2025

Google ScholarTM

Check

Altmetric


All documents in the "Unitus Open Access" community are published as open access.
All documents in the community "Prodotti della Ricerca" are restricted access unless otherwise indicated for specific documents