CNBP; D. melanogaster; Drosophila melanogaster; ODC; genetics; genomics; human; myotonic dystrophy 2; neuroscience; polyamine; translation; CNBP protein, Drosophila; Drosophila Proteins; Polyamines; RNA-Binding Proteins; Spermidine; Putrescine; Animals; Animals, Genetically Modified; Cell Line; Down-Regulation/physiology; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Gene Expression Regulation/drug effects; HEK293 Cells; Humans; Motor Activity/genetics; Motor Activity/physiology; Muscle, Skeletal/metabolism; Myotonic Dystrophy/genetics; Myotonic Dystrophy/metabolism; Polyamines/metabolism; Protein Biosynthesis; Putrescine/pharmacology; RNA Interference; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Spermidine/pharmacology; Down-Regulation; Gene Expression Regulation; Motor Activity; Muscle, Skeletal; Neuroscience (all); Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Medicine; General Neuroscience
Abstract :
[en] Microsatellite expansions of CCTG repeats in the cellular nucleic acid-binding protein (CNBP) gene leads to accumulation of toxic RNA and have been associated with myotonic dystrophy type 2 (DM2). However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA-binding protein that regulates translation and is required for mammalian development. Here, we show that depletion of Drosophila CNBP in muscles causes ageing-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscles from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Coni, Sonia ; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Falconio, Federica A; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy ; Department of Life Sciences Imperial College London South Kensington campus, London, United Kingdom
Marzullo, Marta ; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy ; IBPM CNR c/o Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
Munafò, Marzia ; European Molecular Biology Laboratory (EMBL) Epigenetics & Neurobiology Unit, Campus Adriano Buzzati-Traverso, Monterotond, Italy
Zuliani, Benedetta ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Gene Expression & Cancer ; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
Mosti, Federica; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy ; Department of Neurobiology, Duke University Medical Center, Durham, United States
Fatica, Alessandro; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
Ianniello, Zaira; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
Bordone, Rosa; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Macone, Alberto; Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
Agostinelli, Enzo; Department of Sensory Organs, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy ; International Polyamines Foundation 'ETS-ONLUS', Rome, Italy
Perna, Alessia; Department of Neuroscience, Fondazione Policlinico Gemelli IRCCS, University Cattolica del S. Cuore, Roma, Italy
Matkovic, Tanja; Freie Universität Berlin, Institute for Biology and Genetics, Berlin, Germany
Sigrist, Stephan ; Freie Universität Berlin, Institute for Biology and Genetics, Berlin, Germany
Silvestri, Gabriella; Department of Neuroscience, Fondazione Policlinico Gemelli IRCCS, University Cattolica del S. Cuore, Roma, Italy ; Department of Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della testa-Collo, UOC Neurologia, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Rome, Italy
Canettieri, Gianluca ; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy ; International Polyamines Foundation 'ETS-ONLUS', Rome, Italy ; Pasteur Institute, Fondazione Cenci-Bolognetti, Rome, Italy
Ciapponi, Laura ; Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
AFM-Téléthon [FR] AIRC - Associazione Italiana per la Ricerca sul Cancro [IT] Sapienza - Sapienza Università di Roma [IT] Istituto Pasteur-Fondazione Cenci Bolognetti
Funding text :
This work was supported by AFM Telethon (French Muscular Dystrophy Association, project 21025). AIRC (Associazione Italiana Ricerca Cancro IG 17575), Sapienza University grant RM1181642798C54A and Italian Ministry of Education, Universities and Research, Dipartimenti di Eccellenza-L (232/2016), Istituto Pasteur, Fondazione Cenci-Bolognetti, Rome Italy. We thank Vittorio Padovano for his contribution in generating the mouse anti-dCNBP antibody. We thank Gianluca Cestra for critical reading of the manuscript.
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