| Autor: |
Rossi S; Institute of Translational Pharmacology (IFT), National Research Council (CNR), 00133 Rome, Italy.; Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy., Di Salvio M; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), 00185 Rome, Italy., Balì M; Department of Biology and Biotechnology, University of Rome 'La Sapienza', 00185 Rome, Italy., De Simone A; Department of Biology and Biotechnology, University of Rome 'La Sapienza', 00185 Rome, Italy., Apolloni S; Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy., D'Ambrosi N; Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy.; Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy., Arisi I; Institute of Translational Pharmacology (IFT), National Research Council (CNR), 00133 Rome, Italy.; European Brain Research Institute 'Rita Levi-Montalcini', 00161 Rome, Italy., Cipressa F; Department of Ecological and Biological Science, University of Tuscia, 01100 Viterbo, Italy., Cozzolino M; Institute of Translational Pharmacology (IFT), National Research Council (CNR), 00133 Rome, Italy., Cestra G; Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy.; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), 00185 Rome, Italy.; Department of Biology and Biotechnology, University of Rome 'La Sapienza', 00185 Rome, Italy. |
| Abstrakt: |
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. |
