title: Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS.
abstract: A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS.
authors: Institute of Translational Pharmacology, CNR, 00133 Rome, Italy Laboratory of Neurochemistry, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy.
authors: Simona
authors: S
authors: Rossi
authors: Institute of Translational Pharmacology, CNR, 00133 Rome, Italy.
authors: Alessia
authors: A
authors: Serrano
authors: Laboratory of Neurochemistry, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy.
authors: Valeria
authors: V
authors: Gerbino
authors: Department of Biochemical Sciences "A. Rossi Fanelli", University of Rome "Sapienza", Rome 00185, Italy.
authors: Alessandra
authors: A
authors: Giorgi
authors: Department of Biochemical Sciences "A. Rossi Fanelli", University of Rome "Sapienza", Rome 00185, Italy.
authors: Laura
authors: L
authors: Di Francesco
authors: Laboratory of Neurochemistry, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy.
authors: Monica
authors: M
authors: Nencini
authors: Laboratory of Neurochemistry, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy.
authors: Francesca
authors: F
authors: Bozzo
authors: Department of Biochemical Sciences "A. Rossi Fanelli", University of Rome "Sapienza", Rome 00185, Italy.
authors: Maria Eugenia
authors: ME
authors: Schininà
authors: Department of Biomedicine and Prevention, University of Rome "Tor Vergata", 00133 Rome, Italy Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors: Claudia
authors: C
authors: Bagni
authors: Institute of Molecular Biology and Pathology, CNR, 00185 Rome, Italy Department of Biology and Biotechnology "Charles Darwin", University of Rome "Sapienza", 00185 Rome, Italy.
authors: Gianluca
authors: G
authors: Cestra
authors: Laboratory of Neurochemistry, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy.
authors: Maria Teresa
authors: MT
authors: Carrì
authors: Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium VIB Center for the Biology of Disease, 3000 Leuven, Belgium Tilmann.Achsel@cme.vib-kuleuven.be mauro.cozzolino@ift.cnr.it.
authors: Tilmann
authors: T
authors: Achsel
authors: Institute of Translational Pharmacology, CNR, 00133 Rome, Italy Laboratory of Neurochemistry, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy Tilmann.Achsel@cme.vib-kuleuven.be mauro.cozzolino@ift.cnr.it.
authors: Mauro
authors: M
authors: Cozzolino
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000073885:C9orf72 Protein; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism; D010766:Phosphorylation; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D019680:Trinucleotide Repeat Expansion
chemical_list: D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D051860:Fragile X Messenger Ribonucleoprotein 1; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C568651:C9orf72 protein, human; C501130:PURA protein, human
keywords: Amyotrophic lateral sclerosis; C9orf72; Stress granules; mRNA