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C9orf72 Toxic Species Affect ArfGAP-1 Function
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 machiner...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416972/ https://www.ncbi.nlm.nih.gov/pubmed/37566088 http://dx.doi.org/10.3390/cells12152007 |
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author | Rossi, Simona Di Salvio, Michela Balì, Marilisa De Simone, Assia Apolloni, Savina D’Ambrosi, Nadia Arisi, Ivan Cipressa, Francesca Cozzolino, Mauro Cestra, Gianluca |
author_facet | Rossi, Simona Di Salvio, Michela Balì, Marilisa De Simone, Assia Apolloni, Savina D’Ambrosi, Nadia Arisi, Ivan Cipressa, Francesca Cozzolino, Mauro Cestra, Gianluca |
author_sort | Rossi, Simona |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10416972 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104169722023-08-12 C9orf72 Toxic Species Affect ArfGAP-1 Function Rossi, Simona Di Salvio, Michela Balì, Marilisa De Simone, Assia Apolloni, Savina D’Ambrosi, Nadia Arisi, Ivan Cipressa, Francesca Cozzolino, Mauro Cestra, Gianluca Cells Article 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. MDPI 2023-08-05 /pmc/articles/PMC10416972/ /pubmed/37566088 http://dx.doi.org/10.3390/cells12152007 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Rossi, Simona Di Salvio, Michela Balì, Marilisa De Simone, Assia Apolloni, Savina D’Ambrosi, Nadia Arisi, Ivan Cipressa, Francesca Cozzolino, Mauro Cestra, Gianluca C9orf72 Toxic Species Affect ArfGAP-1 Function |
title | C9orf72 Toxic Species Affect ArfGAP-1 Function |
title_full | C9orf72 Toxic Species Affect ArfGAP-1 Function |
title_fullStr | C9orf72 Toxic Species Affect ArfGAP-1 Function |
title_full_unstemmed | C9orf72 Toxic Species Affect ArfGAP-1 Function |
title_short | C9orf72 Toxic Species Affect ArfGAP-1 Function |
title_sort | c9orf72 toxic species affect arfgap-1 function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416972/ https://www.ncbi.nlm.nih.gov/pubmed/37566088 http://dx.doi.org/10.3390/cells12152007 |
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